Curcumin in Fibrosis Treatment: A Review

Abstract

Fibrosis, marked by excessive accumulation of extracellular matrix (ECM) components, ultimately leads to dysfunction and failure of multiple organs, yet effective therapeutic options remain scarce. Curcumin (CUR), a naturally occurring polyphenol with diverse biological activities, has emerged as a promising candidate for anti-fibrotic intervention. Its designation as Generally Recognized as Safe (GRAS) and widespread use as a food additive offer distinct advantages for its incorporation into functional foods or clinical formulations. Nevertheless, its therapeutic translation is significantly limited by poor aqueous solubility and low systemic bioavailability. In response, a range of advanced drug delivery platforms-such as liposomes, nanoparticles, solid dispersions, and self-microemulsifying drug delivery systems (SMEDDS)-have been developed, markedly improving the solubility, stability, and in vivo bioavailability of CUR. This narrative review systematically summarizes the mechanistic, pharmacokinetic, and safety profiles of CUR in preclinical models of hepatic fibrosis (HF), myocardial fibrosis (MF), pulmonary fibrosis (PF), and renal fibrosis (RF) over the past two decades, focusing on core cellular effectors and signaling pathways. We further highlight recent progress in formulation strategies that potentiate CUR’s anti-fibrotic efficacy, as well as key translational challenges: the pathological divergence between preclinical animal and in-vitro cell models and human fibrotic lesions, plus regulatory barriers limiting clinical adoption. Notably, most available mechanistic observations are derived from short-term pre-clinical experiments, and cannot be directly extrapolated to human chronic fibrotic disease. Despite these hurdles, cumulative preclinical evidence validates CUR’s therapeutic potential as a natural anti-fibrotic agent in experimental settings. Combined with continuous innovation in delivery technology, CUR shows great prospects for developing anti-fibrotic functional foods and clinical therapeutics, yet high-quality human clinical trials are still urgently needed to confirm its real-world efficacy.

Introduction

Fibrosis and Curcumin

Fibrosis is a pathological process that can affect multiple human organs upon sustained exposure to chronic inflammatory responses, oxidative stress, and other disease-driving insults.1–5 Histologically, it is defined by excessive connective tissue deposition, including aberrant extracellular matrix (ECM) accumulation, proliferation of fibroblasts and myofibroblasts, and progressive loss of parenchymal cells. This maladaptive tissue remodeling disrupts organ structure and microvascular integrity, triggering irreversible organ dysfunction and elevated mortality.6–10 Fibrotic diseases affect approximately 5% of the global population each year, with mortality rates climbing, reaching as high as 45% in certain regions,11–14 and imposing substantial economic strain on healthcare systems worldwide. Despite this burden, clinically approved, organ-specific anti-fibrotic therapies remain scarce, highlighting an urgent unmet need for safe, effective, and accessible treatments. As illustrated in Figure 1, these pathological signals converge on canonical pro-fibrotic pathways-including transforming growth factor-β (TGF-β)/Smad, nuclear factor-κB (NF-κB), and mitogen-activated protein kinase (MAPK) cascades-that collectively orchestrate the transdifferentiation of effector cells and drive excessive ECM accumulation, ultimately culminating in organ failure. In this context, herbal medicines represent a promising therapeutic strategy warranting rigorous scientific evaluation.

Figure 1.

Mechanism of fibrosis. Chronic inflammatory stimulation, oxidative damage and repeated parenchymal cell injury serve as initial inducers to activate canonical profibrotic pathways (TGF-β/Smad, NF-κB, MAPK, PPAR family, epigenetic axes etc.). These signaling axes jointly mediate the phenotypic transformation of effector cells (fibroblasts, epithelial cells, HSCs) and boost massive synthesis and abnormal accumulation of ECM components, resulting in tissue structural remodeling and progressive organ failure. Upward arrow indicates upregulation.

Recent translational studies have confirmed natural herbal bioactive compounds as promising anti-fibrotic agents, with multi-target, low-toxicity advantages unmatched by synthetic small-molecule drugs.15–21 Curcumin (CUR), a natural hydrophobic polyphenol primarily derived from turmeric, is widely recognized as a safe food additive and has been used for centuries in culinary traditions, particularly in South Asian cuisine, as a coloring and flavoring agent in dishes like curry, mustard, and pickles.22,23 It is a traditional Chinese medicines that promote blood circulation and remove blood stasis, and have long been used in China to treat pain, inflammation and other diseases Extensive research has demonstrated its diverse biological activities and significant therapeutic potential, including anti-inflammatory, antioxidant, antimicrobial, antitumor, antiangiogenic, and anti-fibrotic effects. Its incorporation into functional foods, dietary supplements, and nutraceuticals has gained attention due to its health-promoting properties and Generally Recognized as Safe (GRAS) status. These properties have led to its clinical investigation for treating various conditions such as inflammation, cancer, diabetes, and cardiovascular diseases.24–28 Due to its favorable efficacy and low toxicity, CUR is a major focus of domestic and international research, particularly in the context of fibrosis treatment and its potential integration into food-based therapeutic strategies. The present review consolidates literature published over the past two decades regarding CUR’s protective effects against four major organ-specific fibrotic disorders, and the source, core bioactivities, and anti-fibrotic scope of CUR are overviewed in Figure 2. These pathological conditions include hepatic fibrosis (HF), myocardial fibrosis (MF), pulmonary fibrosis (PF), and renal fibrosis (RF). This review examines recent advances in CUR’s multi-pathway and multi-target mechanisms, pharmacokinetic characteristics, as well as safety and toxicity profiles. Given its established role in food and its emerging potential in medical applications, this review also explores how CUR’s dual function as a dietary component and a therapeutic agent could be leveraged for preventive and adjunctive treatments. Through critical analysis of completed studies and future perspectives, this work aims to validate CUR’s therapeutic efficacy and safety for clinical use while exploring opportunities to broaden its clinical applications and its incorporation into functional food products for fibrosis management.

Figure 2.

The role of CUR in fibrosis. Turmeric, Radix curcumae, Mustard and Curcumae rhizome are the main sources of CUR. It ameliorates organ fibrosis via suppressing pro-inflammatory mediators (TNF-α, IL-1, IL-6), modulating oxidative stress markers (ROS, SOD, GSH), and targeting multiple keys signaling axes in pulmonary, hepatic, renal and myocardial fibrosis.

Methodology

A literature search covering clinical, in vivo, and in vitro investigations published between 2004 and 2025 was carried out using the PubMed, Web of Science, and Google Scholar databases (final search date: December 2025). The search strings used included combinations of the following terms: “curcumin” AND “fibrosis” AND (“hepatic” OR “liver” OR “myocardial” OR “cardiac” OR “pulmonary” OR “lung” OR “renal” OR “kidney”). Additional search terms were “anti-fibrotic”, “pharmacokinetics”, “safety”, “toxicity”, “bioavailability”, “nanoparticle”, “liposome”, and “delivery system”. Inclusion criteria were: (1) original research articles, reviews, and clinical trials; (2) studies on CUR’s anti-fibrotic effects in hepatic, myocardial, pulmonary, or renal fibrosis; (3) in vivo, in vitro, or clinical studies; (4) English language publications. Exclusion criteria were: (1) non-English articles; (2) conference abstracts; (3) duplicate publications; (4) studies not directly related to CUR’s anti-fibrotic effects. Two independent reviewers screened titles and abstracts, followed by full-text review. Citation tracking was used to find additional relevant material. Using EndNote 20’s automated detection method and manual verification, duplicate records were eliminated. This review is intended as a narrative review, synthesizing and critically evaluating the available evidence rather than performing a quantitative meta-analysis. A total of 175 references were included in this review.

Anti-Fibrotic Effects of CUR

PF

PF constitutes a severe and progressive form of interstitial lung disease characterized by irreversible parenchymal scarring. The pathogenesis of PF involves a complex interplay of repetitive alveolar epithelial injury and sustained activation of pro-fibrotic signaling pathways.29 These pathological mechanisms promote the persistent activation and differentiation of fibroblasts into myofibroblasts, accompanied by dysregulated cellular processes including proliferation, migration, and resistance to apoptosis. Consequently, this leads to ECM accumulation and progressive architectural distortion of lung tissue.30 The resulting fibrotic scar tissue replacement of normal lung parenchyma ultimately culminates in irreversible respiratory dysfunction, representing the hallmark pathological feature of end-stage PF.

TGF-β Pathway

TGF-β functions as a pivotal molecular switch that coordinates essential cellular functions, including survival, proliferation, differentiation, and metabolic regulation, through its extensive signaling networks.31 Under normal physiological conditions, TGF-β activation serves as a critical mediator of tissue repair, facilitating proper wound healing and inflammatory responses. However, in PF, this tightly controlled system becomes profoundly dysregulated, with TGF-β signaling transitioning into a state of pathological overactivation. This sustained hyperactivation triggers two key fibrogenic processes, the induction of epithelial-mesenchymal transition (EMT) and the pathological accumulation of ECM components.32 These interconnected mechanisms create a self-perpetuating cycle of fibrogenesis that drives disease advancement. The fundamental involvement of TGF-β in PF pathogenesis has consequently established it signaling pathway as a primary target for developing novel anti-fibrotic therapies.

Extensive research has consistently demonstrated CUR’s potent anti-fibrotic effects in PF models through TGF-β pathway modulation.33–36 The compound exerts its therapeutic action by suppressing TGF-β-mediated differentiation of lung fibroblasts into collagen-producing myofibroblasts, effectively interrupting the fibrotic cascade. Detailed mechanistic investigations using TGF-β2-stimulated mouse lung fibroblasts revealed a clear dose-response relationship, with CUR concentrations ranging from 5 to 50 μM progressively decreasing both Collagen type I (Co I) secretion and α-smooth muscle actin (α-SMA) expression.37 Complementary studies in human alveolar epithelial A549 cells further established CUR’s protective capacity, showing its ability to prevent paraquat-induced EMT through concurrent downregulation of TGF-β and α-SMA.34

Inflammatory Pathway

While inflammation is an essential physiological process for tissue repair, prolonged inflammatory stimulation can evolve into chronic inflammation that drives fibrotic progression.38 This sustained inflammatory response has emerged as a key pathogenic mechanism and important therapeutic target in PF.

Multiple preclinical studies have demonstrated CUR’s ability to modulate inflammatory pathways in PF models. In ovalbumin/alum-challenged asthmatic mice, low-dose CUR (5 mg/kg) exhibited dual anti-inflammatory and anti-fibrotic effects by inhibiting NF-κB activation, reducing inflammatory cell infiltration (eosinophils and neutrophils), and suppressing matrix metalloproteinases (MMP)-2/9 activity, thereby preventing airway remodeling.39 In bleomycin(BLM)-induced PF models, CUR (75 mg/kg) showed comprehensive therapeutic effects by downregulating pro-inflammatory cytokines (interleukin-17A (IL-17A), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6)) and c-Jun N-terminal kinase (JNK)-mediated MMP expression while enhancing fibrinolytic activity through urokinase-type plasminogen activator (uPA) and its receptor (uPAR) system activation.40 The anti-inflammatory efficacy of CUR was further confirmed in silica-induced silicosis models, where intranasal administration (5 mg/kg) reduced pulmonary infiltration of eosinophils, neutrophils, and macrophages.41 At higher doses (75 mg/kg), CUR demonstrated potent suppression of key inflammatory mediators, including chemokine (C-X-C motif) ligand 1 (CXCL1), interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2), and IL-17A through modulation of AMP-activated protein kinase α (AMPKα)-COX-2 and NF-κB signaling pathways. These findings collectively highlight CUR’s ability to interrupt the inflammatory cascade that drives excessive tissue repair and subsequent fibrotic lesion formation in pulmonary tissues.42,43

Fibroblasts Proliferation and Differentiation

Fibroblasts play a central role in PF pathogenesis as the primary ECM-producing cells. When activated by pro-fibrotic mediators, these cells transform into highly synthetic myofibroblasts that drive excessive collagen deposition and pathological matrix remodeling.44 CUR has shown remarkable efficacy in disrupting this fibrotic cascade through multiple mechanisms.

CUR (0–20 μM) potently inhibits fibroblast activation in a dose- and time-dependent manner, as evidenced by suppressed cyclin D1 and α-SMA expression along with G0/G1 cell cycle arrest in vitro. These cellular effects translated to therapeutic outcomes in BLM-challenged mice, where CUR attenuated alveolar septal thickening and slowed IPF progression.45 Further mechanistic investigations demonstrated CUR’s (0–10 μM) ability to block TGF-β1-driven fibroblast differentiation through peroxisome proliferator-activated receptor γ (PPAR-γ)-dependent upregulation of cathepsins B/L, achieving >95% reduction in α-SMA and >50% decrease in Co I expression.35 The anti-fibrotic activity of CUR was consistently observed across experimental models, with 30 μM treatment enhancing cathepsin K/L expression while reducing fibroblast migration by 45% in human fetal lung fibroblasts. Prolonged CUR administration (200 mg/kg/d) decreased collagen deposition by 29% in BLM-treated mice.36 Additional studies using TGF-β2-stimulated mouse lung fibroblasts confirmed CUR’s (5–50 μM) dose-dependent suppression of proliferation and complete inhibition of myofibroblasts differentiation at 50 μM, as shown by reduced collagen secretion and α-SMA expression.37 These findings collectively establish CUR as a multifaceted inhibitor of fibroblast activation and ECM overproduction in PF.

Apoptosis Pathway

The apoptotic loss of lung epithelial cells represents a fundamental pathogenic event in PF, serving as both an initial trigger and sustained driver of disease progression. This process establishes a pro-fibrotic microenvironment through multiple mechanisms, including compromising epithelial barrier integrity, releasing profibrotic mediators, and recruiting inflammatory cells that collectively promote fibroblast activation and subsequent differentiation into myofibroblasts.46,47 Paradoxically, while epithelial apoptosis initiates fibrosis, the pathological persistence of PF relies on the apoptosis-resistant phenotype of activated fibroblasts and myofibroblasts.48 This dual pathogenesis highlights the therapeutic imperative to simultaneously protect epithelial cells from apoptotic death while selectively inducing apoptosis or functional inhibition of pathogenic fibroblasts.

Experimental evidence demonstrates CUR’s capacity to address both aspects of this apoptotic dysregulation. In BLM-injured alveolar epithelial cells, CUR (20 μM) exerted cytoprotective effects by reducing IL-17A expression, caspase-mediated apoptosis, and epithelial migration capacity, collectively preventing the transition from acute injury to chronic fibrosis.49 Conversely, in fibroblasts, CUR exhibited pro-apoptotic activity by upregulating cathepsins K/L while suppressing TGF-β1 expression.36 These findings were substantiated in vivo, where CUR treatment in BLM-challenged mice increased TUNEL-positive fibroblasts in lung tissue, correlating with enhanced tissue repair and fibrosis resolution.36 This bidirectional modulation of apoptotic pathways underscores CUR’s unique therapeutic potential in PF.

PERK Pathway

The double-stranded RNA-dependent protein kinase (PKR)-like ER kinase (PERK)-mediated endoplasmic reticulum stress response plays a multifaceted role in PF pathogenesis by driving epithelial apoptosis, amplifying pro-fibrotic signaling, and sustaining myofibroblasts activation.50,51 At concentrations of 5 μM in vitro and 30 mg/kg in vivo, CUR treatment inhibits both endothelin-1 and thrombin-induced fibroblasts differentiation while ameliorating BLM-induced PF. This protective effect is mediated through PERK signaling suppression, resulting in marked down-regulation of α-SMA and Co IV expression.52

MiR-29a-3p/DNMT3A Pathway

Emerging evidence reveals a critical regulatory relationship between the miR-29 family and pro-fibrotic mediators in PF, with miR-29 expression inversely correlated with TGF-β1 and connective tissue growth factor levels.53,54 The DNA methyltransferase 3A (DNMT3A), highly expressed in pulmonary fibroblasts and epithelial cells, has been identified as a key epigenetic regulator that influences fibrosis progression by controlling α-SMA expression and fibroblasts-myofibroblasts transition.55 CUR (25 mg/kg) exhibits potent epigenetic modulation in PF by coordinately up-regulating miR-29a-3p while suppressing both nuclear and mitochondrial DNMT3A expression. This dual action results in down-regulation of Collagen type I Alpha 1 chain (COL1A1), fibronectin-1 (FN-1), and mitochondrial respiratory chain complexes, ultimately attenuating BLM-induced ECM remodeling through the miR-29a-3p/DNMT3A axis.56

In summary, CUR exhibits broad-spectrum anti-fibrotic activity against PF, and its multi-level regulatory network is summarized in Figure 3. At the level of common signaling pathways, CUR generally inhibits TGF-β/Smad signaling, thereby blocking the differentiation of pulmonary fibroblasts into myofibroblasts and the secretion of collagen; simultaneously, by inhibiting NF-κB activation and downregulating pro-inflammatory factors such as TNF-α, IL-17A, and IL-6, it alleviates the chronic inflammatory microenvironment in the lungs. Regarding lung-specific pathways, CUR can reduce alveolar epithelial cell apoptosis by inhibiting PERK-mediated endoplasmic reticulum stress; it can also regulate the miR-29a-3p/DNMT3A epigenetic axis to suppress ECM remodeling and mitochondrial dysfunction. Furthermore, CUR exhibits a unique bidirectional regulatory effect on apoptosis in PF, protecting alveolar epithelial cells from apoptosis while promoting the apoptotic clearance of activated fibroblasts. All above mechanistic observations are derived from in-vitro cell experiments (pre-activated fibroblasts, A549 cell line) and short-term BLM-induced rodent PF models. These experimental systems only partially mimic human idiopathic PF and possess important pathological differences: human PF develops over years with multifactorial etiology, whereas BLM injury represents an acute toxic stimulus. The effective CUR concentrations applied in cell culture and animal dosages are often difficult to achieve via conventional oral administration in human subjects. Therefore, these pre-clinical results cannot be directly extrapolated to human PF treatment, and high-quality clinical evidence remains absent to validate these pathways in patients. However, although these studies have identified several potential mechanisms, the biological relevance and clinical translational potential of these findings remain uncertain, highlighting the need for more comprehensive studies on the precise molecular targets and therapeutic mechanisms of CUR in a disease-relevant context.

Figure 3.

The effects of CUR on the PF. CUR targets epigenetic modification, endoplasmic reticulum stress, TGF-β profibrotic cascade, inflammatory response and cell apoptosis. Curcumin elevates miR-29a-3p to repress DNMT3A, and further down-regulates FN1 and COL1A1 to restrain DNA-methylation-driven fibroblast activation. It blocks PERK-mediated profibrotic signals, mitigates TGF-β-triggered excessive ECM deposition, and dampens NF-κB, JNK-related inflammatory responses in alveolar epithelial cells and inflammatory immune cells. Moreover, CUR modulates Cathepsins K/L to trigger myofibroblast apoptosis. Downward arrow indicates downregulation; ┥indicates inhibition; → indicates promotion.

HF

HF represents a maladaptive reparative response of the liver to diverse chronic hepatic insults. This pathological process is characterized by heightened synthesis, insufficient degradation, and pathological deposition of ECM. Hepatic stellate cells (HSCs) are recognized as the principal cellular source responsible for ECM production within the liver, and their activation is widely considered the central pathogenic mechanism driving HF.57–59 Following liver injury, HSCs undergo a phenotypic transition from a quiescent state to an activated myofibroblasts-like state in response to multiple profibrogenic stimuli. This activation triggers heightened production and excessive deposition of ECM components, culminating in the formation of fibrotic scar tissue that progressively replaces functional hepatic parenchyma, thereby advancing the development and progression of HF.59

TGF-β/Smad Pathway

The TGF-β/Smad signaling pathway serves as a central molecular driver of HSCs activation and subsequent ECM accumulation in HF.57 Experimental evidence demonstrates that CUR administration at doses of 200–300 mg/kg and 10–60 μM effectively disrupts this pathogenic cascade through multiple mechanisms. Treatment with CUR resulted in down-regulation of both TGF-β and Smad3 expression, accompanied by reduced mRNA levels of key fibrotic markers, including α-SMA, Co I, and FN. These molecular changes promoted HSCs’ apoptosis while inhibiting HSCs’ proliferation, ultimately leading to marked attenuation of alcohol-induced hepatic fibrogenesis.60 The findings highlight CUR’s ability to target multiple nodes within the TGF-β/Smad signaling axis, suggesting its potential as a multifaceted therapeutic agent for HF.

PPAR-α/γ Pathways

PPARs, comprising the PPAR-α, PPAR-γ, and PPAR-β subtypes, represent a family of ligand-activated nuclear transcription factors critically regulating glucose/lipid homeostasis, cellular proliferation, and differentiation processes.61 In HF, PPAR-α exerts hepatoprotective effects via multiple mechanisms, including facilitation of fatty acid β-oxidation, attenuation of oxidative stress, and suppression of cholestasis, while concurrently modulating extracellular signaling cascades to indirectly inhibit HSCs activation.62 Conversely, PPAR-γ up-regulation directly attenuates HSCs proliferation, reduces α-SMA and Co I expression, and induces apoptosis in activated HSCs.63

CUR (0–30 μM) demonstrated concentration-dependent antagonism of Wnt signaling following PPAR-γ activation. It suppressed oxidized LDL-induced expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), Co I, α-SMA, and key profibrotic genes (connective tissue growth factor (CTGF), TGF-β receptor type I (Tβ-RI), and type II (Tβ-RII)) in HSCs, thereby attenuating HSCs activation.64 CUR (10, and 15 μM) further inhibited oxidative stress and HSCs activation by activating the AMPK signaling pathway. This mechanism up-regulated PPAR-γ coactivator-1α, which subsequently stimulated PPAR-γ and superoxide dismutase-2 expression while suppressing Co I mRNA levels.65 CUR-mediated PPAR-γ activation reverses advanced glycosylation end products (AGEs) -induced suppression of the AGE-R1 promoter, thereby attenuating AGEs-stimulated HSCs activation and proliferation.66 Additionally, CUR modulates the PPAR-γ/p53 axis to induce G0→S phase cell cycle arrest in HSCs, simultaneously inhibiting proliferation and promoting senescence in activated HSCs.67 HSCs represent the primary cellular source of delta-like homolog 1 (DLK1), which epigenetically silences PPAR-γ expression to suppress HSCs activation.68 Furthermore, CUR orchestrates PPAR-γ-mediated suppression of sinusoidal angiogenesis in HF. This occurs through downregulation of endothelial cell markers (CD31, vWF, and CD34) and pro-angiogenic regulators (vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR-2), and platelet-derived growth factor receptor β (PDGFR-β)), mechanistically linked to inhibition of the PDGFR-β/extracellular signal-regulated kinase (ERK), mammalian target of rapamycin (mTOR), focal adhesion kinase (FAK)/Ras homolog family member A (RhoA) signaling cascades.69

In summary, CUR-mediated PPAR-γ activation confers therapeutic benefit in HF through multipronged mechanisms, including ameliorating oxidative stress, suppressing HSCs’ proliferation and differentiation, attenuating pathological sinusoidal angiogenesis, and inducing senescence of activated HSCs.

Leptin Receptor Pathway

Leptin, encoded by the obesity (ob) gene, requires signaling through its cognate receptor LEPR (Ob-R) to mediate metabolic responses. Critically, activated HSCs produce leptin, which subsequently orchestrates an autocrine activation loop. Ob-R upregulates ECM remodeling genes, thereby driving HSCs activation and promoting HF pathogenesis.70,71 In activated HSCs, CUR (5–30 μM) dose-dependently attenuated leptin-induced oxidative stress by reducing reactive oxygen species (ROS) generation and lipid peroxidation while enhancing glutamate-cysteine ligase activity and suppressing HSCs activation through PPAR-γ-mediated inhibition of Ob-R phosphorylation and receptor gene expression.72 In another study, CUR inhibited leptin-induced glucose accumulation in HSCs and blocked energy supply-dependent activation of HSCs by interrupting the leptin-activated insulin receptor substrate (IRS), phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and glucose transporter type 4 (GLUT4) signaling pathway, blocking GLUT4 translocation, glucokinase activation, and conversion of glucose to glucose-6-phosphate.73 In conclusion, CUR inhibits HF by suppressing leptin-mediated activation of HSCs.

Hh Pathway

The Hedgehog (Hh) signaling pathway contributes to fibrogenesis by exacerbating HF through modulation of energy metabolism, proliferation, activation, and senescence of HSCs.74 CUR (100–300 mg/kg and 10–30 μM) demonstrated dose-dependent suppression of Hh signaling, reducing mRNA expression of cyclin D1, cyclin D2, and Bcl-2, while inhibiting profibrotic factors. Concurrently, CUR impeded HSCs glycolysis and disrupted metabolic pathways to reduce energy supply, thereby exerting anti-HF effects.75 CUR (400 mg/kg and 20 μM) partially up-regulated PPAR-γ expression by inhibiting DLK1 via blockade of Sonic Hedgehog (Shh) signaling, ultimately suppressing HSCs activation and attenuating HF.76

TLR Pathway

Toll receptors (TLRs) constitute a critical class of pattern recognition receptors within the innate immune system. Hepatic injury triggers TLR-mediated activation of inflammasomes and release of pro-inflammatory cytokines, establishing a state of persistent hepatic inflammation that drives fibrogenesis.77,78 CUR (200 mg/kg) demonstrates potent anti-fibrotic effects by modulating this pathway; it down-regulates expression of TLR2 and TLR4, while concurrently suppressing mRNA levels of high-mobility group box 1, a key damage, associated molecular pattern recognized by TLRs. This dual action attenuates the inflammatory cascade in carbon tetrachloride (CCl₄)-induced rat liver injury.79 Mechanistically, CUR exerts its effects partly through inhibition of the myeloid differentiation primary response 88 (MyD88)-dependent signaling pathway downstream of TLR activation. By suppressing MyD88 protein expression, CUR subsequently inhibits NF-κB translocation and reduces recruitment of inflammatory mediators and infiltrating cells to hepatic tissue. Importantly, this pathway modulation coincides with promoted apoptosis of HSCs,80 suggesting a multifunctional therapeutic mechanism. The induction of HSCs apoptosis represents a promising strategy for interrupting the self-perpetuating cycle of fibrogenesis in chronic liver disease.

CBR Pathway

Based on extensive research into HF, cannabinoid Receptors (CBR) exhibit distinct and critical roles in its pathogenesis. Specifically, inactivation of CB₁R attenuates hepatic fibroblast accumulation, while CB₂R activation inhibits the proliferation of human hepatic myofibroblasts and promotes fibroblast apoptosis, collectively suppressing HF progression.81,82 CUR (100, 200, and 400 mg/kg) efficacy against HF through targeted binding to CB₁R in CCl₄-induced HSCs. This interaction inhibited CB₁R expression and subsequently suppressed the expression of key fibrogenic markers, α-SMA, α (1) procollagen, and FN, thereby reducing ECM production.83 However, contrasting results emerged in a bile duct ligation-induced HF rat model. While CUR treatment (20 mg/kg) effectively reduced transaminase levels, total bilirubin, and NF-κB expression, it exhibited minimal impact on CB₁R and CB₂R expression.84 This disparity highlights the complex and context-dependent nature of CUR’s interaction with the endocannabinoid system. The observed differential effects may be attributed to variations in experimental models (toxic vs cholestatic injury) and significantly different dosing regimens. Consequently, the precise modulatory effects of CUR on CBR signaling warrant further in-depth investigation, although its involvement cannot be definitively excluded given the model and dose-dependent outcomes observed.

DNA Methylation Pathway

DNA methylation represents a critical epigenetic mechanism that mediates heritable changes in gene expression during HSCs activation, driving the development of aberrant cellular phenotypes and fibrotic progression.85 This epigenetic reprogramming establishes DNA methylation modulation as a promising therapeutic target for hepatic fibrosis. CUR (200 mg/kg) demonstrates potent anti-fibrotic efficacy through multi-layered epigenetic regulation, effectively suppressing Co I/II/III and α-SMA expression. Mechanistically, CUR upregulates miR-29b to inhibit DNMT3b-mediated methylation of the phosphatase and tensin homolog (PTEN) promoter, thereby restoring PTEN expression and its inhibitory effects on ECM deposition and HSCs activation.86 Additionally, CUR interferes with fibrotic progression by down-regulating methionine adenosyltransferase 2B through inhibition of p38 MAPK signaling, an effect that may directly alter the DNA methylation landscape in activated HSCs.87 These findings position CUR as a multifaceted epigenetic modulator capable of targeting DNA methylation at multiple regulatory levels to counteract hepatic fibrogenesis.

ERK Pathway

The ERK pathway critically regulates hepatic myofibroblasts activity by controlling proliferation, differentiation, and cell death processes.88 CUR treatment (400–1200 mg/kg) effectively reduced CCl₄-induced liver damage, improving histological architecture while suppressing Co III, α-SMA, and hypoxia-inducible factor-1α (HIF-1α) expression. These combined effects attenuated hepatic fibrosis through ERK pathway inhibition.89

KCs

Following hepatic injury, liver-resident Kupffer cells (KCs) rapidly secrete pro-inflammatory and pro-fibrotic mediators, including IL-1β, TNF-α, and TGF-β. This cascade drives HSCs activation and further amplifies monocyte infiltration via KCs-derived chemotactic factors, thereby exacerbating hepatic inflammation while potentiating HF.90 In CCl₄-induced HF models and in utilizing murine macrophage cell lines, CUR (200 mg/kg and 2.5–10 μM) inhibited KCs activation and suppressed expression of monocyte-recruiting chemokines monocyte chemoattractant protein-1 and C-C motif chemokine ligand 7. Consequently, CUR reduced infiltration of pro-inflammatory Ly6C^hi monocytes and attenuated their release of inflammatory and fibrogenic mediators, ultimately mitigating liver inflammation and fibrogenesis.91

NK Cells

Natural killer (NK) cells attenuate HF through targeted clearance of senescent cells within fibrotic liver tissues.92 Experimental validation utilizing both a CCl₄-induced fibrotic model in ICR mice and co-culture systems with LX2 HSCs and NK-92 cell lines demonstrated that CUR (300 mg/kg and 20 μM) suppresses hepatic fibrogenesis. This occurs through the induction of HSCs’ senescence, thereby potentiating their immunologically mediated elimination by NK cells.93

Autophagy Pathway

In the context of HF development, autophagy exhibits dual roles. In hepatocytes, macrophages, and hepatic sinusoidal endothelial cells, autophagy serves to limit hepatocyte damage, suppress inflammatory factor release, and maintain hepatic homeostasis, thereby exerting an inhibitory effect on HF. Conversely, in HSCs, autophagy promotes fibrosis by enhancing HSCs’ proliferation, ECM secretion, and energy supply.94,95

In a separate study involving LX-2 cell treatment, CUR (20 μM) alleviated HF by inhibiting autophagy in activated HSCs through PIK/AKT/mTOR signaling activation. This intervention suppressed LX-2 cell activity, reduced Co I and α-SMA synthesis, and increased apoptotic protein Bcl-2-associated X protein (Bax) and cleaved caspase 3 expression, thereby promoting hepatocyte apoptosis and attenuating fibrotic processes.96

CXCL12/CXCR4 Pathway

The C-X-C chemokine receptor type 4/C-X-C motif chemokine ligand 12 (CXCR4/CXCL12) axis critically drives HF pathogenesis by promoting the expression of α-SMA and Co I. This signaling cascade induces HSCs activation, proliferation, and migration, thereby exacerbating ECM deposition and disease progression.97 CUR attenuates fibrogenesis by suppressing α-SMA, RhoA, and Co I expression via targeted inhibition of the CXCR4/CXCL12 pathway. Experimental evidence from in vitro and in vivo models confirms that CUR abrogates HSCs activation, proliferation, and migratory capacity, collectively ameliorating HF.98

Anti-Capillarization Pathway

Capillarization, marked by loss of fenestration in hepatic sinusoidal endothelial cells and aberrant basement membrane deposition, represents a pathologic dedifferentiation of liver sinusoidal endothelial cells that precedes HF. Critically, restoring liver sinusoidal endothelial cells differentiation drives HSCs’ quiescence and fibrosis regression.99,100 CUR (200 mg/kg) attenuates this process in CCl₄-induced fibrosis by down-regulating proangiogenic factors, reducing microvessel density (CD31⁺), suppressing endothelial defenestration, and inhibiting basement membrane protein deposition. Consequently, CUR mitigates capillarization and thereby ameliorates experimental HF.101

CUR can synergistically intervene in the progression of HF through multiple signaling pathways, as comprehensively illustrated in Figure 4. Among these, the TGF-β/Smad, PPAR-α/γ, TLR4/NF-κB and MAPK/ERK pathways serve as common core pathways, primarily exerting their protective effects by inhibiting the activation of key fibrotic effector cells in the organ and alleviating oxidative stress and chronic inflammation; The liver possesses unique, specific regulatory pathways: the leptin Ob-R metabolic pathway, the Hh glycolytic metabolic axis, the cannabinoid CB₁R/CB₂R pathway, the CXCL12/CXCR4 chemokine axis, and the miR-29b/DNMT3b DNA methylation pathway. Additionally, the liver possesses unique immune regulatory mechanisms (KCs and NK cells clearing senescent HSCs), a pathway for reversing sinusoidal capillarization, and an autophagy-regulating axis involving PI3K/AKT/mTOR. Unlike other organs, where fibroblasts serve as the primary target cells, the core driver of HF is HSCs. All of the aforementioned unique pathways regulate HSCs proliferation, glucose and lipid metabolism, senescence, and apoptosis, and the effects of these pathways are model-dependent. However, although CUR exhibits these multi-pharmacological characteristics, its multi-target nature also introduces dose-dependent unpredictability. Furthermore, existing pre-clinical data are mostly generated from acute carbon tetrachloride- and alcohol-induced liver injury animal models, while evidence from metabolic or cholestatic HF models, as well as large-animal studies, remains notably insufficient. It should be emphasized that CCl₄ and alcohol-intoxication models reflect acute toxic liver insults and cannot fully recapitulate the slow, multifactorial progression of human chronic HF driven by virus, metabolic syndrome, or non-alcoholic steatohepatitis. The relatively high dosages used in rodent experiments are hard to replicate by routine oral intake in humans. Therefore, future studies designing CUR combination therapy trials should distinguish between viral, alcohol-induced, and metabolic HF. These studies should be integrated with advanced technologies such as liver organoids, single-cell sequencing, and spatial multi-omics to dynamically analyze the evolving HSCs-immune cells-endothelial cells microecosystem, rather than relying solely on acute rodent injury models. This comprehensive approach will provide in-depth and comprehensive evidence for the anti-fibrotic efficacy of CUR before clinical translation.

Figure 4.

The effects of CUR on the HF. CUR exerts hepatoprotective and anti-fibrotic effects by targeting epigenetic regulators (DNMT3b, miR-29b), TGF-β/Smad profibrotic signaling, insulin-metabolic IRS/PI3K/Akt-AMPK-PGC-1α-PPAR-α/γ axis, ROS-related oxidative injury, HMGB1-TLR4-MyD88-NF-κB inflammatory pathway, Hedgehog and Wnt/FAK/RhoA cascades. Meanwhile, CUR reverses pathological sinusoidal angiogenesis and capillarization, and triggers autophagy-mediated cell clearance. Downward arrow indicates downregulation; ┥indicates inhibition; → indicates promotion.

MF

MF is the accumulation of ECM and collagen deposition resulting from the over-activation and proliferation of fibroblasts and their further differentiation into myofibroblasts, which form non-contractile mature scar tissues replacing the damaged cardiomyocytes to maintain the structural integrity of the heart.102 Ultimately, the loss of cardiac function, regardless of ejection fraction, is one of the major factors contributing to the death of patients after heart failure.103 The dysregulation of MAPK, MMP, α-SMA, CTGF, and immune cells, as that of the renin-angiotensin-aldosterone system (RAAS), is closely involved in this process.104

TGF-β Pathway

CUR (20 μM) pretreatment in TGF-β1-stimulated rat myocardial fibroblasts effectively inhibited myofibroblasts transdifferentiating by reducing Smad2/p38 phosphorylation and suppressing α-SMA/Co I expression.105 Multiple studies consistently show that CUR downregulates TGF-β1 signaling, decreasing Smad activation and key fibrotic markers,106–111 demonstrating its ability to attenuate myofibroblasts activation and ECM overproduction.

PPAR-γ Pathway

PPAR-γ deficiency exacerbates angiotensin II (Ang II)-induced MF and potentiates TGF-β-mediated fibrotic responses.112,113 CUR (100 mg/kg) attenuated ECM overproduction, myocardial fibroblasts proliferation, systolic blood pressure elevation, and left ventricular collagen deposition in spontaneous hypertensive rats.114

MAPK Pathway

The MAPK signaling cascade, comprising JNK, p38 MAPK, and ERK subfamilies, exhibits pathological hyperactivation during myocardial fibrogenesis. This activation drives dysregulated cardiac fibroblast proliferation, myofibroblasts transdifferentiating, and pro-inflammatory mediator production, thereby accelerating ECM remodeling.102

In streptozotocin (STZ)-induced diabetic rats, CUR (100 mg/kg) attenuated MF through suppression of p38 MAPK and ERK1/2 phosphorylation, concomitantly inhibited protein kinase C (PKC)-α/β₂ activation, while reducing hyperglycemia, NAD(P)H levels, and malondialdehyde (MDA) accumulation, indicative of mitigated oxidative stress. Concurrent down-regulation of TGF-β, bone morphogenetic proteins, and NF-κB activity diminished inflammatory mediator release and ECM deposition.107 Complementary analyses demonstrated CUR’s inhibition of TGF-β1-induced myocardial fibroblasts transdifferentiating via p38/ERK pathway blockade, and modulating cytoskeletal regulators including CDK1.105,110 These collective findings establish CUR as a pleiotropic modulator that ameliorates fibrotic remodeling through coordinated MAPK pathway redox homeostasis restoration and suppression of fibroblasts activation.

MMPs/TIMPs Pathways

MF involves dysregulated ECM homeostasis, where MMP overexpression drives pathological ECM degradation while excessive tissue inhibitors of matrix metalloproteinases (TIMP) activity inhibits physiological collagen turnover, collectively promoting maladaptive remodeling.115,116 In post-infarct rats, CUR (150 mg/kg) treatment suppressed MMP-2/9 activity, preserved matrix integrity, and attenuated fibrotic lesion formation, thereby increasing viable myocardial mass.106 Complementary studies demonstrated dose-dependent CUR administration concurrently down-regulated MMP-9 and TIMP-1 expression, while enhancing collagen catabolism. This dual regulation attenuated both isoproterenol-induced fibrosis and Ang II-stimulated myocardial fibroblasts proliferation.109

SIRT1 Pathway

Silent information regulator sirtuin 1 (SIRT1), an evolutionarily conserved NAD⁺-dependent deacetylase, critically regulates cellular metabolism, proliferation, survival, differentiation, autophagy, and oxidative stress responses, while providing cardio-protection against ischemia/reperfusion injury.117,118 CUR administration (100 mg/kg) attenuated MF through SIRT1 activation, down-regulated pathological collagen deposition while enhancing physiologic ECM turnover, inhibiting myocardial fibroblasts proliferation and migration.119 These findings establish SIRT1 agonism as a novel therapeutic strategy for mitigating maladaptive fibrotic remodeling.

Macrophages

Persistent M1 macrophage infiltration during myocardial injury sustains inflammatory and profibrotic signaling. Although partial polarization toward reparative M2 macrophages occurs, this compensatory response proves inadequate to prevent sustained myofibroblasts activation and pathological ECM deposition.120,121 In myocardial infarction models, CUR (50–100 mg/kg and 20 μM) reduced inflammatory cytokine release (IL-6, IL-1β, and TNF-α) and promoted macrophage apoptosis, thereby attenuating collagen deposition.111 Similarly, dietary CUR (150 mg/kg) diminished macrophage infiltration and myofibroblasts proliferation in hypertensive rats, alleviating MF.108

As summarized above, CUR exerts its anti-myocardial fibrotic effects by regulating the myocardial microenvironment through multiple targets, and these multi-layered regulatory mechanisms are visually illustrated in Figure 5. At the level of common signaling pathways, CUR inhibits the TGF-β/Smad2/3 and p38 MAPK/ERK signaling pathways, thereby blocking the transdifferentiation of myocardial fibroblasts into myofibroblasts; by activating PPAR-γ to alleviate angiotensin II–induced MF; and by inhibiting NF-κB to reduce inflammatory damage to the myocardium. MF does not involve the core pathological process of EMT; rather, the core pathological changes are the excessive activation of myocardial fibroblasts and the infiltration of inflammatory macrophages. CUR regulates myocardial oxidative metabolism and balances the matrix degradation enzyme system via SIRT1, specifically improving myocardial scarring induced by stress, diabetes, and myocardial infarction. However, most existing experiments use drug-induced or surgical short-term heart failure animal models, which recapitulate acute cardiac injury instead of the slowly progressive, multi-comorbid fibrotic remodeling occurring in human chronic heart failure patients. Animal intervention dosages are substantially higher than feasible human oral exposure. Direct inference from these pre-clinical findings to human anti-fibrotic therapeutic outcomes should be made with great caution.

Figure 5.

The effects of CUR on the MF. CUR suppresses PKC-α/β₂-p38 MAPK-ERK1/2 signaling to restrain macrophage-derived inflammatory response. It inhibits TGF-β₁/Smad2 cascade and elevates PPAR-γ, thereby decreasing the expression of profibrotic mediators including CTGF, PAI-1, α-SMA, FN and collagens. Meanwhile, CUR mitigates oxidative injury and activates SIRT1-dependent protective pathway, and remodels TIMP-1/MMP-2/9 equilibrium to restrain excessive ECM. Downward arrow indicates downregulation; ┥indicates inhibition; → indicates promotion.

RF

RF represents a common terminal pathological manifestation across multiple chronic kidney diseases. During fibrogenesis, diverse renal cell populations, including resident fibroblasts, tubular epithelial cells, parietal epithelial cells, infiltrating lymphocytes, macrophages, and activated myofibroblasts,122 orchestrate disease progression through interconnected mechanisms. These encompass dysregulated ECM synthesis/degradation, EMT, cell cycle arrest, cellular senescence, apoptosis, profibrotic extracellular vesicle secretion, paracrine signaling, and fibroblasts-to-myofibroblasts differentiation. Cumulatively, these processes drive progressive fibrotic scarring.123 CUR demonstrates therapeutic potential by modulating these cellular interactions and molecular pathways to attenuate or reverse fibrotic remodeling.

TGF-β Pathway

Experimental studies have demonstrated the anti-fibrotic effects of CUR in renal cells through multiple mechanisms. At a concentration of 625 ng/mL, CUR alleviates high glucose-induced fibrosis by suppressing TGF-β secretion, down-regulating the expression of fibrotic markers (F-actin, α-SMA, FN, and Co I), and reducing MMP-2/9 enzymatic activity.124 Further mechanistic investigations reveal that CUR dose-dependently inhibits Smad pathway transduction, thereby decreasing plasminogen activator inhibitor-1 (PAI-1) and α-SMA expression to counteract TGF-β-mediated profibrotic signaling in human proximal tubular cells (HK-2).125 In addition, CUR targets TGF-β to prevent hypermethylation of the klotho promoter, subsequently restoring klotho expression while reducing PAI-1, α-SMA, and Co I levels, ultimately attenuating cyclosporine A-induced RF.126 These findings collectively highlight CUR’s potential as a therapeutic agent for RF through its multifaceted modulation of TGF-β signaling pathways.

PPAR-γ Pathway

Based on accumulating evidence, PPAR-γ agonists mitigate RF by suppressing fibroblasts activation and attenuating epithelial inflammation in murine models.127 Mechanistically, CUR (1–20 μM) functions as a PPAR-γ agonist by facilitating its nuclear translocation and inhibiting phosphorylation, effects mirrored by the reference agonist rosiglitazone. This activity is mediated through ERK pathway inhibition, as ERK blockade similarly prevents PPAR-γ phosphorylation. Through PPAR-γ activation, CUR down-regulates profibrotic markers (α-SMA, PAI-1, TβRI, and TβRII) while restoring E-cadherin expression, thereby antagonizing TGF-β1-driven EMT in renal tubular cells.128 This suppression of EMT critically reduces myofibroblasts generation, constituting a primary mechanism for CUR’s anti-fibrotic efficacy.

TLR4/NF-κB Pathways

TLR4/NF-κB constitutes a canonical inflammatory signaling axis wherein TLR4 activation triggers NF-κB nuclear translocation, driving transcription of pro-inflammatory genes (such as TNF-α, IL-1β, and IL-6) and amplifying cytokine production.129,130 Sustained activation of this pathway propagates RF through chronic inflammatory stimulation.131 CUR attenuates TLR4/NF-κB signaling, suppresses inflammatory mediators and fibrotic proteins, and dose-dependently preserves renal function, evidenced by reduced serum creatinine and blood urea nitrogen (BUN). This multi-target inhibition mitigates inflammation, blocks EMT, and ameliorates renal interstitial fibrosis in unilateral ureteral obstruction murine models.132

Nrf2-keap1 Pathway

The nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) signaling axis governs basal and inducible expression of multiple antioxidant response genes, playing a pivotal role in mitigating cellular oxidative damage.133,134 Renal dysregulation of this pathway exacerbates oxidative stress and inflammatory responses.135,136 In 5/6 nephrectomy rat models, CUR (75 mg/kg) attenuated oxidative stress, inflammation, renal functional decline, and fibrosis through Nrf2-Keap1 modulation. This was evidenced by reduced plasma creatinine, BUN, MDA, NF-κB and FN expression, and elevated creatinine clearance.137 Furthermore, CUR (5–20μM) dose and time-dependently up-regulated Nrf2 protein expression and its downstream effector heme oxygenase-1 (HO-1). This activation inhibited high glucose-induced EMT in renal tubular epithelial cells, as reflected by enhanced E-cadherin and suppressed α-SMA expression, thereby exerting anti-fibrotic effects.138

RGMb Pathway

Repulsive guidance molecules (RGMs), a family of glycosylphosphatidylinositol-anchored cell membrane proteins, critically regulate tissue and organ development.139 RGMb, a member of this family, demonstrates high expression in murine kidney tissue and mediates renal tubular injury through suppression of E-cadherin expression and induction of tubular epithelial cell apoptosis.140,141 Mechanistically, RGMb overexpression up-regulates key fibrogenic effectors, thereby accelerating fibroblast proliferation and apoptosis. CUR treatment reverses these RGMb-driven pro-fibrotic responses and attenuates established RF.142

ADAMTS Pathway

Disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) enzymes, classified within the zinc-dependent metalloproteinase superfamily alongside MMPs, modulate tissue remodeling in fibrotic pathologies by governing cellular processes including proliferation, migration, apoptosis, and ECM degradation.143 In TGF-β1-stimulated NRK-49F rat renal fibroblasts, CUR (30 μM) attenuated fibrotic progression by epigenetically up-regulating ADAMTS18 expression through promoter demethylation. This suppressed the expression of fibrosis markers, reduced ECM accumulation, and decreased apoptosis, collectively ameliorating RF.144

Caveolin-1 Pathway

Caveolin-1, a key member of the caveolin protein family, plays a crucial role in cell-ECM interactions through caveolae formation145 and regulates cell proliferation and migration by modulating TGF-β signaling and ECM remodeling.146,147 In diabetic rats, CUR (100 mg/kg) effectively suppressed podocyte EMT by reducing the expression of fibroblast-specific protein 1 and α-SMA, while preserving glomerular basement membrane integrity and stabilizing the levels of caveolin-1 and β-catenin.148 Furthermore, CUR exerted renoprotective effects by inhibiting oxidative stress, thereby mitigating high glucose-induced podocyte apoptosis.149 These anti-fibrotic effects are mechanistically associated with CUR’s ability to attenuate caveolin-1 phosphorylation, highlighting its therapeutic potential in RF.

Gut Microbiota

Gut microbial dysbiosis drives RF via the gut–kidney axis. Renal dysfunction promotes urea flux into the gut, depleting short-chain fatty acids (SCFAs)-producing commensals while enriching toxin-generating bacteria, thereby disrupting intestinal tight junctions and increasing systemic translocation of indoxyl sulfate, p-cresyl sulfate, and trimethylamine N-oxide (TMAO). These circulating uremic toxins induce renal oxidative stress and activate NF-κB, NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, and TGF-β/Smad signaling, which promote tubular epithelial–mesenchymal transition and myofibroblasts activation, ultimately exacerbating ECM deposition.150,151 Conversely, microbially derived SCFAs reinforce intestinal barrier integrity and suppress renal inflammatory-fibrotic cascades, functioning as endogenous renoprotective metabolites.152

In a rat model of hyperuricemic nephropathy induced by adenine combined with potassium oxalate,153 hyperuricemia-induced kidney damage disrupts the homeostasis of the gut microbiota, leading to an enrichment of toxin-producing pathogenic bacteria such as Escherichia and Shigella, as well as Bacteroides species, while the abundance of short-chain fatty acid-producing bacteria, such as Lactobacillus and Ruminococcus species, decreases significantly. This is accompanied by reduced expression of the intestinal tight junction proteins zonula occludens-1 (ZO-1), occludin, and claudin-1, leading to increased intestinal permeability, accumulation of circulating endotoxins, sustained activation of renal inflammation, and induction of tubulointerstitial fibrosis. CUR (200 mg/kg) intervention reversed the aforementioned microbial dysbiosis, restored intestinal barrier integrity, reduced serum uric acid, creatinine, and endotoxin levels, and alleviated renal collagen deposition, indicating that it improves renal injury and fibrotic lesions by regulating the gut microbiota and repairing the intestinal barrier. In a rat model of chronic kidney disease following a 5/6 nephrectomy,154 the abundance of the Firmicutes phylum was reduced, the Proteobacteria phylum was abnormally elevated, gut microbiota α-diversity was decreased, and inflammatory damage was observed in the colonic mucosa; following CUR (200 mg/kg) intervention, the abundance of the Firmicutes phylum rebounded, beneficial short-chain fatty acid-producing bacteria such as Muribaculaceae and the NK4A136_group within the Spirochaetaceae family were enriched. This suppressed the excessive activation of the Lipopolysaccharide (LPS)/TLR4/NF-κB pathway caused by dysbiosis, downregulated the TGF-β1/Smad pro-fibrotic signaling pathway, and reduced the deposition of α-SMA and Co I, thereby alleviating RF in chronic kidney disease. Furthermore, in a mouse model of unilateral ureteral obstruction,155 CUR (200 mg/kg) increased plasma acetate concentrations by enriching short-chain fatty acid-producing microbiota. Acetate specifically inhibits the S100 calcium-binding protein A8/A9-TLR4 signaling axis in macrophages, blocking macrophage-to-myofibroblasts transdifferentiation and reducing the secretion of pro-inflammatory factors in the kidneys, thereby suppressing excessive ECM accumulation.

CUR exerts renoprotective anti-fibrotic bioactivities via multi-layered mechanisms, which are graphically depicted in Figure 6. CUR not only blocks EMT and fibroblast activation in renal tubular epithelial cells by inhibiting TGF-β/Smad signaling; it also alleviates oxidative stress-induced damage by activating the Nrf2-Keap1/HO-1 antioxidant pathway; reduces chronic renal inflammation by inhibiting the TLR4/NF-κB inflammatory axis; and suppresses EMT and ECM deposition by activating PPAR-γ. Furthermore, regarding kidney-specific pathways, CUR can reverse RGMb-overexpression-induced renal tubular epithelial cell apoptosis and E-cadherin inhibition; promote ADAMTS18 promoter demethylation through epigenetic regulation to enhance ECM degradation; and inhibit caveolin-1 phosphorylation to protect podocytes from high-glucose-induced EMT and apoptosis. Furthermore, CUR can reduce the burden of renal inflammation and fibrosis by repairing the intestinal barrier, regulating gut microbiota metabolites, and reducing the systemic accumulation of uremic toxins. Collectively, in-vitro cell assays and UUO, 5/6 nephrectomy, adenine-induced rodent models support above-mentioned mechanistic hypotheses. Nevertheless, these rodent models produce rapid, acute-on-chronic kidney injury and do not faithfully mirror human chronic kidney disease-related renal fibrosis, which evolves over many years under complex metabolic and vascular risk factors. Large-animal experimental data and rigorous human clinical evidence are still absent. Therefore, mechanistic outcomes observed in pre-clinical settings cannot be automatically assumed to translate into renoprotective anti-fibrotic benefits in patients.

Figure 6.

The effects of CUR on the RF. CUR blocks EMT and ECM accumulation through PPAR-γ, ADAMTS18 and caveolin-1 phosphorylation-dependent pathways. It mitigates inflammatory injury by restraining TLR4/NF-κB-driven pro-inflammatory cytokine release. CUR activates Nrf2-Keap1-HO-1 antioxidant axis to scavenge ROS. In addition, CUR elevates RGMb and represses Dnmt1-induced Klotho promoter hypermethylation, thereby suppressing TGF-β-Smad2/3 profibrotic cascades. Upward arrow indicates upregulation; Downward arrow indicates downregulation; ┥indicates inhibition; → indicates promotion.

Pharmacokinetics

CUR’s therapeutic application is fundamentally limited by its adverse physicochemical properties, including poor aqueous solubility and chemical instability, which collectively contribute to inadequate intestinal absorption, rapid systemic metabolism, and consequently low oral bioavailability.156–159 Pharmacokinetic evidence demonstrates that oral administration of 1 g/kg in rats produces plasma concentrations below 0.02 µg/mL within 30 min, with approximately 75% of the administered dose excreted unmetabolized in feces.160 When administered orally at 2 g/kg in rats, the peak serum concentration reaches 1.00 ± 0.26 µg/mL at 0.75 h post-administration, followed by rapid elimination within 1 hour, whereas this same dosage in humans yields virtually undetectable serum levels.161 In contrast, intraperitoneal injection (0.1 g/kg) in mice achieves substantially higher plasma exposure of approximately 15 µg/mL,162 and comparative pharmacokinetic analysis reveals a 60-fold greater plasma concentration following intravenous administration (10 mg/kg; 0.36 ± 0.05 µg/mL) versus oral dosing (500 mg/kg; 0.06 ± 0.01 µg/mL).163 Despite exhibiting broad tissue distribution, CUR demonstrates limited tissue penetration, with rodent studies showing preferential accumulation in the intestines (177.04 µg/g), spleen (26.06 µg/g), liver (26.90 µg/g), and kidneys (7.51 µg/g) over the brain (0.41 µg/g) 1 h post-intravenous injection (0.1 g/kg), indicating inefficient biological barrier permeation. Hepatic metabolism serves as the primary elimination pathway through reductive biotransformation, generating pharmacologically active metabolites including dihydrocurcumin, tetrahydrocurcumin, and hexahydrocurcumin,164,165 with terminal elimination occurring predominantly via biliary-fecal excretion (70–75% of administered dose) and minimal renal clearance (<10%) of conjugated metabolites.166

Safety and Toxicity Evaluation

CUR, a natural bioactive compound widely present in the food spice turmeric, has become a focal point in both nutritional and medical research due to its significant health-promoting properties, including anti-inflammatory, antioxidant, and anti-tumor activities.167 As a common food additive and coloring agent (E100) that has been safely consumed for centuries in traditional diets, particularly in South Asian cuisine, CUR’s transition from culinary use to therapeutic applications is supported by its exceptional safety profile.168 Extensive toxicological studies confirm that CUR exhibits minimal acute and chronic toxicity, with adverse reactions being rare and typically mild even at high consumption levels. This outstanding safety record, combined with its food-grade status, positions CUR uniquely among natural compounds with both nutritional and medicinal value.169 For instance, a study assessing its safety found that healthy volunteers administered a single oral dose as high as 2000 mg of CUR showed no associated toxic side effects.161 In more rigorous randomized, double-blind, controlled trials, subjects receiving long-term oral CUR at doses ranging from 250 mg/d to 1500 mg/d similarly reported no adverse events attributable to CUR, confirming its excellent tolerability at common doses.168,170 Strikingly, even with prolonged exposure to ultra-high doses, safety remains impressive, in a 3-month clinical trial, subjects taking up to 8000 mg/d orally experienced only a few isolated reports of mild gastrointestinal discomfort, such as nausea and diarrhea.171 It should be noted that other studies observed events like fever, throat infection, abnormal liver enzyme levels, or hematological changes within groups taking oral CUR.25,172 However, the investigators explicitly stated that a causal link between these occurrences and CUR intake could not be established. They concluded these events were more likely attributable to the subjects’ underlying disease states or other confounding factors rather than a direct toxic effect of CUR itself. CUR’s safety is further corroborated in high-risk populations undergoing combination therapy. In a Phase I/II clinical study of CUR combined with gemcitabine for patients with gemcitabine-resistant pancreatic cancer, the Phase I dose-escalation phase revealed no dose-limiting toxicities caused by CUR. Based on this, the phase II study employed a high-dose regimen of 8000 mg per day orally. The results showed no evidence of cumulative CUR toxicity even at this high dosage. Notably, some patients continued treatment for up to 6 months without developing any significant or severe toxic reactions.173

Collectively, the substantial body of clinical evidence strongly supports CUR’s outstanding safety profile. Both short-term administration of high single doses and long-term (even extending for several months) daily intake of high doses (up to 8 grams/d) are associated with excellent tolerability and safety, with adverse reactions being mild and uncommon. This provides a crucial safety foundation for its deeper investigation and potential therapeutic applications.

Different Dosage Forms of CUR

Oral free CUR is severely limited by unfavorable physicochemical properties: extremely low aqueous solubility, rapid gastrointestinal degradation and extensive first-pass metabolism, resulting in oral systemic bioavailability lower than 1%. Free CUR cannot penetrate dense cross-linked ECM in fibrotic scars to reach therapeutic effective concentrations at lesion sites. Fibrotic microenvironments contain multiple physical and biological barriers, such as hypoxic scar tissue, hepatic sinusoidal capillarization, and large quantities of activated HSCs, myofibroblasts and injured tubular epithelial cells. Traditional nanocarrier research mostly only improves CUR solubility and plasma drug exposure, without verifying scar penetration and specific uptake by pro-fibrotic effector cells, limiting their translational value for anti-fibrotic therapy.174–176

Traditional egg phosphatidylcholine-cholesterol liposomes are the earliest mature lipid-based CUR delivery system, which can enhance CUR aqueous solubility by 700–12,000-fold and prolong blood circulation half-life. However, they lack active targeting capacity for fibrotic tissue and distribute non-selectively in abdominal organs after intravenous injection.177,178 In diet-induced non-alcoholic steatohepatitis mouse models, unmodified CUR liposomes are passively engulfed by lipid-rich F4/80⁺ hepatic dendritic cells and KCs via lipid uptake pathways, shifting dendritic cells to tolerogenic phenotypes and inhibiting NF-κB/JNK inflammatory cascades to relieve hepatic steatosis and inflammatory infiltration. Nevertheless, plain liposomes barely enter activated HSCs—the core ECM-secreting cells in HF—and fail to cross dense collagen ECM barriers, only alleviating liver inflammation rather than directly inhibiting fibrogenesis.179

Cholinized polymer-functionalized lipid nanoparticles (CP-LNPs) overcome the delivery bottleneck of conventional liposomes for hepatic fibrotic lesions. Relying on liver choline uptake physiological tropism and positive surface charge, CP-LNPs achieve nearly 100% hepatic accumulation within 10 min after tail vein injection, avoiding widespread off-target systemic distribution. In CCl₄-induced HF mice, CUR-loaded CP-LNPs efficiently penetrate hepatic ECM and are internalized by both LX-2 activated HSCs and injured L02 hepatocytes. In vitro cellular assays confirm this formulation arrests HSC proliferation and migration, downregulates α-SMA expression, and clears excessive mitochondrial ROS in hepatocytes, realizing dual hepatoprotective and anti-fibrotic effects. Compared with oral free CUR requiring effective doses of 60–400 mg/kg, CP-LNPs significantly reduce hepatic collagen deposition, serum transaminase elevation and intrahepatic ROS accumulation at an equivalent CUR dose of only 10 mg/kg, lowering systemic drug exposure risks. Unlike ordinary nanocarriers merely optimizing pharmacokinetic parameters, CP-LNPs have been fully validated in vivo HF models to possess ECM penetration and dual effector cell targeting functions, combining anti-inflammatory and anti-fibrotic activity. Their clinical translation limitations lie in intravenous-only administration and complex polymer synthesis processes restricting large-scale industrial production.180

Polymeric micelles modified with variable surface ligands display tissue-selective recognition capacity for fibrotic lesions across multiple organs, while unmodified polyethylene glycol (PEG) micelles only enhance CUR solubility and extend blood circulation retention time with poor ECM penetration ability; after systemic circulation, most blank micelles are cleared by splenic and hepatic macrophages without enrichment in scar tissues, only generating weak systemic antioxidant effects and unable to restrain local myofibroblasts activation.181,182 Ligand-functionalized micelles overcome this defect via lesion-specific binding: mitochondria-targeted mitochondria-targeted triphenylphosphonium-PEG-poly (ε-caprolactone) micelles selectively accumulate in damaged hepatocytes and suppress collagen secretion by HSCs in liver injury models, folate-modified Pluronic F127 micelles target folate receptor-overexpressed renal tubular epithelial cells under oxidative stress to alleviate TGF-β1-triggered epithelial-mesenchymal transition and tubulointerstitial fibrosis after acute kidney injury, MMP-2 responsive cleavage micelles disassemble within MMP-rich pulmonary fibrotic lesions to release CUR and inhibit the proliferation of pulmonary myofibroblasts, and macrophage membrane biomimetic micelles home to myocardial infarct fibrotic regions to block the TGF-β/Smad signaling cascade and reduce scar formation post infarction. All ligand-responsive micelle types have obtained consistent anti-fibrotic phenotypic verification in corresponding organ fibrosis animal models, different from non-targeted micelles that merely adjust plasma drug levels, despite the drawbacks of complex surface modification processes and unstable batch performance during mass production.183–185

Solid dispersions adopt hydrophilic polymer carriers such as polyvinylpyrrolidone and hydroxypropyl methylcellulose to disrupt CUR crystal structures and drastically improve oral dissolution rates, fundamentally resolving the solubility defect of oral CUR preparations,186 yet they exert no tissue targeting or ECM penetrating functions from the perspective of fibrotic disease treatment. After oral administration, CUR released from solid dispersions evenly enters systemic circulation without preferential accumulation in fibrotic organs, resulting in moderately elevated plasma CUR concentrations but insufficient drug levels within collagen scars to suppress myofibroblasts activation. Existing preclinical data demonstrate solid dispersions can only relieve mild systemic oxidative stress and fail to reverse established ECM deposition in liver, lung or renal fibrosis models, belonging to formulations that solely optimize pharmacokinetic properties without lesion-targeted delivery capacity, only suitable for auxiliary intervention of mild subclinical fibrosis rather than progressive fibrotic lesions, with prominent strengths of complete oral administration compatibility and mature, low-cost mass production technology.187

Self-microemulsifying drug delivery systems (SMEDDS) spontaneously form microemulsions after contacting gastrointestinal fluid, featuring high CUR encapsulation efficiency and complete oral absorption that elevates oral CUR bioavailability by approximately 117 times relative to free CUR.188 Yet conventional untargeted SMEDDS share identical limitations with solid dispersions without fibrotic tissue enrichment capability. Most SMEDDS research only evaluates solubility and plasma concentration indicators, lacking in vivo validation of lesion drug accumulation and anti-fibrotic efficacy; limited rodent data show high-dose oral SMEDDS slightly reduce hepatic fat accumulation but produce negligible effects on collagen deposition in CCl₄-induced HF, as CUR cannot cross dense hepatic ECM to reach HSCs.189 Liver-specific ligand modified SMEDDS are still at cell experimental stages, with no in vivo fibrosis model verification reported to date. SMEDDS are suitable for long-term dietary adjuvant use but cannot serve as core therapeutic formulations for progressive organ fibrosis due to the absence of lesion penetration and effector cell targeting functions.157

Different from systemic oral or intravenous nanocarriers that commonly suffer from off-target toxicity and insufficient local drug retention within thick fibrotic scars, implantable biomimetic double-network hydrogels represent a localized delivery strategy specially designed for RF injury repair. The gelatin-CUR-zinc dual-network (GCS) hydrogel is fabricated with polydopamine surface immobilized Ac-SDKP tetrapeptide to co-load CUR and Ac-Ser-Asp-Lys-Pro (Ac-SDKP) for sustained local release at nephrectomy-induced renal fibrotic sites;190 CUR-Zinc coordination bonds stabilize CUR against rapid in vivo degradation, and the three-dimensional porous hydrogel scaffold breaks through dense renal interstitial ECM barriers to continuously deliver CUR to injured tubular epithelial cells and renal interstitial fibroblasts. In vitro cellular assays confirm GCS hydrogel eliminates intracellular ROS and inhibits TGF-β1-triggered HK2 epithelial-mesenchymal transition and NRK-49F collagen synthesis; in partial nephrectomy rat models, in situ implanted hydrogels continuously release CUR to block renal fibrosis progression while facilitating angiogenesis and renal tubular regeneration, lowering serum creatinine and urea nitrogen levels and reducing intra-renal collagen deposition area. Unlike circulating nanomedicines that rely on passive lesion enrichment via blood flow, implant hydrogels achieve 100% localized CUR retention at fibrotic sites and completely avoid systemic side effects, though their application scope is restricted to local surgical repair due to invasive implantation operations and unsuitable for chronic diffuse fibrotic diseases requiring repeated drug delivery.191

Current CUR nanomedicine research exists a widespread homogenization flaw that most studies only characterize particle size, solubility and plasma pharmacokinetic parameters while ignoring verification of fibrotic scar penetration and profibrotic cell-specific uptake, leading to overestimated clinical transformation potential of ordinary nanomaterials. Even formulations with optimized in vitro pharmacokinetic indicators cannot be regarded as anti-fibrotic therapeutic agents unless their ability to overcome pathological ECM barriers and suppress myofibroblasts activation is validated in disease-specific animal models. Two major research shifts are required for future CUR delivery system development. First, researchers ought to construct organ-specific fibrotic microenvironment responsive nanocarriers sensitive to MMP, ROS or pH signals, which disassemble selectively within scar tissue to elevate local CUR concentration and lower systemic off-target exposure, such as chitosan-based inhaled CUR micro-particles designed for idiopathic pulmonary fibrosis and inflammation-responsive macrophage membrane micelles targeting myocardial fibrotic zones. Second, multi-functional co-delivery platforms combining CUR with anti-fibrotic small molecules or regenerative peptides should be exploited; the renal GCS hydrogel co-loaded with CUR and Ac-SDKP has proven that antioxidant and tissue-repairing agents exert synergistic anti-fibrotic effects to break the single CUR therapeutic ceiling.

Discussion

Although extensive preclinical in vitro and in vivo investigations have confirmed the broad-spectrum anti-fibrotic capacity of CUR across pulmonary, hepatic, myocardial and renal fibrotic lesions (Table 1), its clinical transformation is hindered by multifaceted obstacles arising from its multi-target pharmacological characteristics, dual identity as food ingredient and therapeutic candidate, inherent pharmacokinetic defects, limitations of preclinical experimental models, immature targeted delivery technology, and imperfect clinical research frameworks.

Table 1.

Role of CUR in Fibrotic Diseases

Disease	In vivo/vitro	Animal/Cell Model	Dosage	Duration	Mode of Administration	Described Effects	Pathways	References
PF	In vivo	OVA+alum-induced Balb/c mice	5 mg/kg	22 d	Intranasal	↓: ROS, EPO, MPO, histamine, nitricoxide, IgE, eosinophil, neutrophil, collagen, MMP-2, MMP-9, NF-κB	/	[39]
	In vivo	SiO2-induced Female mice (Swiss strain)	5 mg/kg	3 weeks	Intranasal	↓: neutrophils, α-SMA, ROS, alveolar macrophages, Nitrite, EPO, MPO, MMP-9 ↑: TIMP-1	/	[41]
	In vivo	BLM-induced C57BL/6 male mice	75 mg/kg	2 weeks	Intraperitoneal	↓: collagen, IL-17A, TNF-α, IL-6, PAI-1, α-SMA, MMP-2, MMP-9, JNK ↑: uPA, uPAR	JNK	[40]
	In vivo	OVA+alum-induced Balb/c mice	5 mg/kg	5 weeks	Intranasal	↓: leukocyte, TIMP-1, eosinophils, neutrophils, MMP-9, collagen, hydroxyproline ↑: ASM mass	/	[42]
	In vivo	OVA+alum-induced Balb/c mice	10 mg/kg	23 d	Intraperitoneal	↓ROS, NO, neutrophils, eosinophils, IL-5, histamine, IgE, MMP-9, HDAC8, α-SMA, NF-κB, MAPK	/	[43]
	In vitro	A549 cells	30 μM	24 h	/	↓: ROS, α-SMA, TGF-β, MMP-9 ↑: E-cadherin	TGF-β	[34]
	In vivo vitro	BLM-induced C57BL/6 mice Human lung fibroblasts cell	300 mg/kg 1, 5, 10, 20 μM	3 weeks 72 h	Gavage	↓: cyclinD1, α-SMA, Smad2/3, ERK1/2, collagen, hydroxyproline	TGF-β, Smad2/3, ERK1/2	[45]
	In vitro	CCD-19Lu fibroblasts	0-10 μM	48 h	/	↓: TGF-β1, COL1A1, CoLA2, Cystatin C ↑: CatB, CatL, PPARγ	PPARγ/CatB/L	[35]
	In vitro	TGF-β2-stimulated Mouse lung fibroblast cell	5, 25, 50 μM	1 h	/	↓: Co I, α-SMA, PDGFR-β ↑: PPAR-γ	PPAR-γ/ PDGFR-β	[37]
	In vivo	BLM-induced C57BL/6 mice	75 mg/kg	5, 6 d	Intraperitoneal	↓: IL-17A, BALF, P-p53, p53, PAI-I, caspase-3, P-Erk, Ki-67, Fbln5, Sparc, Cd93, Hspg2, STAT, TGF-β	/	[33]
	In vitro	A549	20 μM	24 h	/	↓: IL-17A, p53, PAI-1, caspase-3	p53-PAI-1	[49]
	In vivo/vitro	BLM-induced C57BL/6 mice HFL-1	200 mg/kg 1–30 μM	1, 2, 4 weeks 24, 48, 72 h	Gavage	↓: collagen, TGF-β1 ↑: CatK, CatL, CatB, CatS	CatK, CatL	[36]
	In vivo/vitro	BLM-induced BALB/c mice WI-38 cells	30 mg/kg 2.5, 5, 10 μM	24 h 30 min	Intraperitoneal	↓: α-SMA, MAPK, CCN2 ↑: miR-19a, miR-19b, miR-26b	PERK, MAPK	[52]
	In vivo/vitro	BLM-induced C57BL/6 mice MRC5	25 mg/kg 50 μM	28 d 24 h	Intraperitoneal	↓: COL1A1, FN1, DNMT3 ↑: miR-29a-3p	miR-29a-3p/DNMT3A	[56]
HF	In vitro	HSCs	0-30 μM	24 h	/	↓:Ob-R, ROS, lipid peroxidation ↑: GSH, GCLc, GCLm, PPAR-γ	PPAR-γ/Ob-R	[72]
	In vitro	HSCs	0-30 μM	Pre 1 h	/	↓: glucose, IRS, PI3K, AKT, p-PKA, GLUT4 ↑:glucokinase, glucose-6-phosphate p-AMPK	IRS/PI3K/AKT/GLUT4	[73]
	In vitro	HSCs	0-30 μM	24 h	/	↓: PDGF-βR, Tβ-RI, LOX-1, Wnt ↑: PPAR-γ	PPAR-γ/Wnt/ LOX-1	[64]
	In vitro	HSCs	0-15 μM	24 h	/	↓: COL1A1 ↑:PGC-1α, AMPK, PPAR-γ, SOD2	AMPK/PPAR-γ/PGC-1α	[65]
	In vitro	HSCs	0-30 μM	24 h	/	↓: COL1A1, α-SMA, PDGF-βR, cyclinD1, Bcl-2, Tβ-RI/II, CTGF, ERK ↑: AGE-R1, PPAR-γ	PPAR-γ/ERK /AGE-R1	[66]
	In vivo/vitro	CCl4-induced male Sprague Dawley rats CCl4 and Ad. Fc-induced male ICR mice HSC-T6 cell	100, 200, 300 mg/kg 300 mg/kg 0–40 μM	8 weeks 8 weeks 24 h	Gavage	↓: α-SMA, COL1A1 ↑: P53, PPAR-γ, G1 cells	PPAR-γ/P53	[67]
	In vivo/vitro	CCl4-induced male Sprague Dawley rats HSCs	100, 200, 400 mg/kg 10–100 μM	8 weeks 24, 48 h	Gavage	↓: αSMA, α(1)procollagen, FN, CD31, vWF, CD34, VEGF, VEGF-R2, PDGF-βR, HIF1α, ERK, PI3K, AKT, mTOR, p70S6K, FAK/RhoA ↑: PPAR-γ	PDGF-βR/ERK, mTOR, FAK/RhoA	[69]
	In vivo/vitro	CCl4-induced male Sprague Dawley rats HSCs	100, 200, 300 mg/kg 10, 20, 30 μM	8 weeks 24 h	Gavage	↓: Shh, Patched, Smo, PFK2, Glut4 ↑: Hhip, CCAAT/enhancer-binding protein α, PPAR-γ	Hh	[75]
	In vivo/vitro	Thioacetamide-treatment Sprague-Dawley rats HSCs	400 mg/kg 0, 10, 15, 20 μM	4 weeks 24 h	Gavage	↓: DLK1, Shh, α-SMA, α(1)procollagen ↑: PPAR-γ	DLK1	[76]
	In vivo	CCl4-induced male Sprague Dawley rats	200 mg/kg	6 weeks	Gavage	↓: ALT, AST, TNF-a, IL-6, MCP-1, HMGB1, TLR4, TLR2	TLR2/4	[79]
	In vitro	HSCs-T6	25 μM	24 h	/	↓: NF-κB, TNF-α, IL-1β, TLR2, TLR4, MyD88	MyD88	[80]
	In vivo	CCl4-induced male Sprague Dawley rats	100, 200, 400 mg/kg	8 weeks	Gavage	↓: α-SMA, α(1)procollagen, FN, CB1R ↑: CBR2	CB1R/CB2R	[83]
	In vivo	Surgical ligation of the common bile duct-induced male Sprague Dawley rats	20 mg/kg	2 weeks	Gavage	↓: ALT, AST, enzyme activities, total bilirubin, COX-2, CB1R ↑: Bcl2	CB1R	[84]
	In vivo/vitro	CCl4-induced male Sprague Dawley rats HSC-T6	200 mg/kg 20 μM	6 weeks48 h	Gavage	↓: AKT, ERK, COL1A1, α2(I)collagen, α3(I)collagen, α-SMA, DNMT3b ↑: PTEN	DNMT3b	[86]
	In vivo/vitro	TAA-induced C57BL/6J male miceHSCs	400 mg/kg 20 μM	4 weeks 24 h	Gavage	↓: MAT2B, α-SMA, p38 MAPK	p38MAPK /MAT2B	[87]
	In vivo/vitro	Oral alcohol-induced Sprague-Dawley male rats HSCs	200, 300 mg/kg 10–60 μM	12 weeks 24 h	Gavage	↓: ALT, AST, Co I, α-SMA, FN, TGF-β, Smad3↑: Smad7	TGF-β/Smad	[60]
	In vivo	CCl4-induced Sprague-Dawley male rats	400, 1200 mg/kg	6 weeks	Gavage	↓: ALT, AST, ALP, Co III, α-SMA, HIF-1α, p-ERK	ERK/HIF-1α	[89]
	In vivo/vitro	CCl4-induced C57/B6 male mice RAW264.7 cells	200 mg/kg 0–80 μM	4 weeks 12 h	Gavage	↓: ALT, AST, Co I, α-SMA, Ly6Chi, IL-1β, TNF-α, GRN, TGF-β1, MCP-1, CCL7, CD86+, KCs	/	[91]
	In vivo/vitro	CCl4-induced male ICR mice LX2 cell line and NK-92 cell	300 mg/kg 20, 40 μM	8 weeks 24 h	/	↑: Hmga1, γ-H2AX, perforin, granzyme B	/	[93]
	In vitro	HSCs line LX-2	20 μM	24 h	/	↓: Co I, α-SMA ↑: Bax, cleaved-caspase3, p-PI3K, p-AKT, C/EBPα, PPAR-γ	PI3K/AKT/mTOR	[96]
	In vivo/vitro	CCl4-induced Sprague-Dawley male rats HSC-T6	50, 100, 200 mg/kg 10–160 μM	8 weeks 24 h	Gavage	↓: ALT, AST, TBIL, HA, LN, PCIII, CXCL12, CXCR4, α-SMA, RhoA, Co I	CXCL12/CXCL4	[98]
	In vivo	CCl4-induced Sprague-Dawley male rats	200 mg/kg	6 weeks	Gavage	↓: ALT, AST, Co I, Co III, α-SMA, HIF-1, VEGF, COX2, PlGF	/	[101]
MF	In vivo	STZ-induced male Sprague-Dawley rats	100 mg/kg	8 weeks	Gavage	↓: PKC-b, p38MAPK, ERK1/2, MEF2, NF-κB, ANP, TGF-β, osteopontin	PKC-MAPK	[107]
	In vitro	TGF-β1-induced Sprague-Dawley rats MF	20 μmoL/L	30 min	/	↓: α-SMA, Co I, Smad2, p38	Smad-2, p38 MAPK	[105]
	In vitro	TGF-β1-induced human MF	20 μmoL/L	1 h	/	↓: α-SMA, Co I, Co III, cyclin B, CDK1, Smad2/3, p38 MAPK, ERK	p38 MAPK/ERK	[110]
	In vivo	Ischaemia-induced male Sprague-Dawley rats	150 mg/kg	1, 3, 5 weeks	Gavage	↓: MDA, proMMP-9, MMP-9, proMMP-2, MMP-2, Co I, Co III, Smad2, Smad3, Smad4, α-SMA ↑: Smad7	/	[106]
	In vivo	Ang II–induced male Sprague Dawley rats	150 mg/kg	2, 4 weeks	Gavage	↓: MAP, AT1, α-SMA, TGF-β1, Smad2, Smad3, Co I ↑: AT2, ACE2	AT1/AT2, ACE2	[108]
	In vivo/vitro	ISO-induced male Sprague-Dawley (SD) rats Ang II–induced rat MF	150, 300mg/kg 10, 20 μmoL/L	4 weeks	Gavage	↓: LVIDd, LVIDs, Co I, Co III, MMP-9, TIMP-1, α-SMA	TGF-β1, MMPs/TIMPs	[109]
	In vivo/vitro	Surgically induced male C57/BL/6J mice macrophages	50,100 mg/kg 1–50 μM	4 weeks	Gavage	↓: IL-6, IL-1β, TNF-α, α-SMA, Vimentin, Periostin, Smad2/3, IL-18	IL18-P-SMAD2/3	[111]
	In vivo/vitro	Male spontaneously hypertensive rats (SHRs)/male Wistar Kyoto (WKY) rats Sprague-Dawley rats MF	100 mg/kg 5, 10, 20 μmoL/L	12 weeks	Gavage	↓: SBP, CTGF, PAI-1, Co III, FN, TGF-β1, Smad2/3 ↑: PPAR-γ	PPAR-γ	[114]
	In vivo/vitro	Surgically induced male C57/BL/6J mice Wistar rats MF	100 mg/kg 5, 10, 15 μM	4 weeks pre 1h	Gavage	↓: Co I, Co III, TGF-β1, MMP-2, MMP-9 ↑: SIRT1	SIRT1	[119]
RF	In vivo/vitro	UUO-induced C57BL/6 male mice HK-2	50 mg/kg 10 ng/mL	2 weeks	Gavage	↓: Scr, BUN, IL-1β, IL-6, TNF-α, α-SMA, TGF-β1, TLR4, p-P65, PI3K, AKT	TLR4/ NF-κB PI3K/AKT	[132]
	In vivo/vitro	5/6 nephrectomy-Sprague-Dawley male mice	75 mg/kg	11 weeks	Gavage	↓: SBP, Keap1, p22phox, MDA, NF-κB, NF-α, COX-2, TGF-β1 ↑: CCr, Nrf2, HO-1, GPx	Nrf2-keap1	[137]
	In vivo/vitro	UUO-induced Sprague-Dawley male rats HK-2	50, 100 mg/kg 10, 20, 30 μM	1 weeks	Gavage	↓: SCr, BUN, TGF-β1, P-Smad2/3, caspase-3, caspase-8, Dragon, Co I, Co IV, vimentin, E-cadherin, α-SMA	RGMb	[142]
	In vitro	NRK-52E	0-20 μM	24, 48 h	/	↓: α-SMA, ↑: E-cadherin, Nrf2, HO-1	Nrf2-HO-1	[138]
	In vitro	HK-2, BHK-21	1-625 ng/mL	24 h	/	↓: F-actin, α-SMA, FN, Co I, MMP-2, MMP-9, ROS, TGF-β	/	[124]
	In vitro	HK-2	10, 20, 50, 100 μM	48 h	/	↓: α-SMA, PAI-1, Smad2	Smad2	[125]
	In vivo/vitro	Cyclosporine A-induced female C57BL/6 mice and HK-2	15 mg/kg 1–20 μM	2 weeks 24 h	Intraperitoneal	↓: α-SMA, PAI-1, Co I, Dnmt1	Hypermethylation of the klotho	[126]
	In vitro	HK-2	1, 10, 20 μM	12 h	/	↓: α-SMA, PAI-1, TβRI, TβR II, ERK, Smad2, Smad3 ↑: E-cadherin, PPAR-γ	ERK/PPAR-γ/TGF-β1	[128]
	In vitro	NRK-49F	0-40 μmoL/L	24 h	/	↓: FN, Co I, α-SMA ↑: cyclin D1, ADAMTS18	ADAMTS18	[144]
	In vivo/vitro	STZ-induced male Wistar rats MPC5	100 mg/kg 1, 5, 10 μM	12 weeks 1 h	Gavage	↓:caveolin-1, fibroblast-specific protein 1, α-SMA, snail 1, ↑: P-cadherin, synaptopodin	Caveolin-1	[148]
	In vivo/vitro	STZ-induced male Wistar rats MPC5	50, 100, 200 mg/kg 1, 5, 10 μM	8 weeks	Gavage	↓: MDA, caspase-3, caveolin-1, ROS ↑: SOD	Caveolin-1	[149]
	In vivo	Adenine and potassium oxonate-induced male Wistar rats	200 mg/kg	8 weeks	Gavage	↓: uric acid, serum creatinine, LPS, BUN, Enterobacteriaceae and Bacteroides ↑:ZO-1, occluding, and claudin-1	/	[153]
	In vivo	5/6 nephrectomy-induced male SD rats	200 mg/kg	12 weeks	Gavage	↓:Scr, BUN, 24-hour urine protein, TGF-β1, Smad2, Smad3, IL-1β, IL-6, LPS, MCP-1, TLR-4, NF-κB, Erysipelotrichales ↑:goblet cells, Oclin, Cldn1, ZO-1, SCFAs	/	[154]
	In vivo/vitro	UUO-induced male C57BL/6 mice LPS-induced Macrophages	200 mg/kg 20 µM	10d	Gavage	↓:α-SMA, Co I, TGF-β1, p-Smad3, F4/80+, Macrophages, S100A8, S100A9, TLR4, MyD88, IRAK4, TAK1 ↑:SCFAs, Firmicutes, Lactobacillus, Prevotella, Allobaculum, Ruminococcus, Claudin-1, Occludin, ZO-1		[155]]

Notes: ↓: downregulation, ↑: upregulation.

The translational obstacle originates from the essential distinction among CUR’s three non-interchangeable identities: natural food-derived bioactive constituent, over-the-counter dietary supplement raw material, and investigational anti-fibrotic therapeutic drug candidate, a point that is often insufficiently emphasized in existing mechanistic studies. It should be highlighted that the GRAS (Generally Recognized as Safe) designation only certifies the safety of curcumin when used as a food additive under routine dietary exposure (approximately 100 mg/day for general human populations). This food-safety qualification cannot be interpreted as evidence supporting anti-fibrotic pharmacological efficacy. Nearly all rodent anti-fibrosis intervention studies adopt dosages higher than 100 mg/kg, generating systemic drug exposure dozens of times higher than the maximum exposure achievable in humans via ordinary diet or conventional-dose dietary supplements. This critical dose-feasibility gap partially explains why human observational and supplement-based clinical studies can only detect mild auxiliary anti-inflammatory effects, whereas no high-quality randomized controlled trial has demonstrated that CUR can reverse established mature fibrotic lesions in human organs.

Further translational barriers are associated with oral bioavailability, in vivo metabolite profiles, drug-drug interaction risks, and insufficient long-term safety evidence. Even for optimized oral formulations, human oral bioavailability of CUR remains intrinsically low. After hepatic uptake, CUR undergoes extensive reductive metabolism to produce dihydrocurcumin, tetrahydrocurcumin, and hexahydrocurcumin; the respective anti-fibrotic contributions of these metabolites in human subjects remain poorly characterized and are rarely separated in pre-clinical animal experiments. CUR is capable of modulating cytochrome P450 enzyme activity, which creates potential drug-drug interaction risks when co-administered with anticoagulants, chemotherapeutic agents, and other medicines metabolized via cytochrome P450 pathways. Such interaction risks are seldom systematically assessed in short-term animal studies. While short-term clinical trials have demonstrated acceptable tolerability, real-world multi-year long-term safety data for high-dose CUR are still limited, especially for vulnerable populations including patients with pre-existing hepatic or renal impairment and patients receiving multiple concurrent medications.

From the regulatory perspective, CUR-related preparations fall into different regulatory tracks corresponding to its three identities. Simple curcumin raw powders, solid dispersions, and self-microemulsifying formulations marketed as dietary supplements follow food-supplement regulatory requirements; these products are not required to provide definitive clinical proof of anti-fibrotic therapeutic efficacy, and commercial products exhibit large batch-to-batch variations in purity, impurity profiles, and excipient composition across global markets. In contrast, injectable nanocarriers, implantable hydrogels and other formulations intended for disease-targeted anti-fibrotic therapy must comply with full-scale pharmaceutical drug-development workflows, including comprehensive pharmacokinetic and toxicological assessments, scalable manufacturing-process validation, stability testing, and sequential Phase I-II-III human clinical trials before obtaining official marketing authorization. Researchers should avoid equating supplement-grade CUR products with investigational therapeutic drug candidates merely because they adopt identical solubility-enhancement technologies.

Compounding this issue, inconsistent industrial manufacturing criteria lead to large variations in purity and auxiliary excipients among commercially available CUR products, and complex dietary matrices rich in fats and other plant polyphenols further alter CUR intestinal absorption efficiency in vivo, such that single-compound cellular and animal experimental data can hardly be directly extrapolated to human dietary intervention scenarios. Accordingly, clear demarcation must be drawn between CUR applied as daily functional food raw material, over-the-counter dietary adjuvant supplement, and experimental prescription anti-fibrotic therapeutic, otherwise researchers risk overstating CUR’s clinical prospects merely based on simplified pre-cellular phenotypic readouts.

Beyond this regulatory and dose-related conflict, CUR’s widely celebrated pleiotropic multi-target activity concurrently constitutes a major impediment to standardized clinical development. On one hand, simultaneous modulation of the TGF-β/Smad, NF-κB, PPAR, Nrf2 and dozens of other interconnected signaling pathways endows CUR with unique advantages for treating heterogeneous fibrotic injuries accompanied by concurrent inflammation and oxidative stress; on the other hand, this overlapping regulatory network obscures the identification of core therapeutic targets and straightforward dose-effect correlations, a stark contrast to synthetic single-target small-molecules whose dosing adjustments can be precisely guided by dynamic biomarker fluctuations. When CUR dosage is modified, hundreds of genes linked to ECM metabolism, inflammatory response and redox homeostasis undergo synchronous upregulation and downregulation, which complicates the design of stratified administration schemes for patients complicated by mixed inflammatory and fibrotic lesions. Regrettably, current mechanistic research largely remains confined to isolated descriptions of individual signaling axes modulated by CUR, while lacking quantitative network pharmacology analysis to weigh the relative contribution of each pathway across distinct organ fibrotic subtypes, which in turn restricts the rational design of CUR-based combination therapies for stratified patient cohorts.

Further exacerbating translational divergence are systemic limitations inherent to conventional pre-clinical research models, whose oversimplified design tends to overestimate CUR’s in-vivo therapeutic efficacy. In-vitro monolayer immortalized cell lines such as A549, LX-2 and NRK-49F fail to recapitulate three-dimensional tissue architecture, dynamic crosstalk between parenchymal and immune cells, as well as dense ECM physical barriers characteristic of human fibrotic microenvironments. The CUR concentrations commonly deployed in cell culture assays are biochemically unattainable via oral administration in humans, rendering many in-vitro inhibitory phenotypes difficult to replicate in living organisms.

In vivo rodent models including BLM-induced PF, CCl₄-triggered HF and UUO-mediated RF predominantly recapitulate acute tissue damage rather than the spontaneous, multi-causal chronic fibrotic progression seen in aging human patients complicated by diabetes, metabolic syndrome or viral hepatitis. Animal experiments uniformly employ young, genetically homogeneous rodents with observation windows limited to several weeks or months, whereas human fibrotic disorders advance gradually over multiple years. What is more, most existing intervention trials adopt CUR monotherapy while ignoring clinical confounders including polypharmacy and age-related organ function decline, which inevitably weakens the reference value of pre-clinical efficacy data for human trial planning. Findings obtained from short-term, high-dose pre-clinical models cannot be directly adopted to formulate human therapeutic regimens.

In parallel, the bulk of nanocarrier formulation research carries a pervasive homogenized flaw, as most studies only characterize particle size, solubility and plasma pharmacokinetic indicators without systematic in-vivo validation of their penetration capacity into fibrotic scars and specific uptake by core profibrotic effector cells such as HSCs and myofibroblasts. Apart from insufficient verification of lesion-targeted delivery efficiency, the potential modulatory effects of blank nanocarrier matrices on inflammatory cytokine networks and ECM remodeling enzymes also remain uncharacterized, thereby creating unquantified long-term safety risks for sustained lesion-targeted administration. Even with substantial improvements in CUR solubility and systemic exposure brought by novel nanocarriers such as liposomes, polymeric micelles and SMEDDS, the two aforementioned bottlenecks still severely hinder real-world clinical translation.

To break the above translational deadlocks, three fundamental paradigm shifts in CUR anti-fibrosis research are urgently required. First, construct cross-scale multi-dimensional research frameworks: patient-derived organoids and organ-on-a-chip models should be applied to reconstruct human-like fibrotic microenvironments, paired with spatial multi-omics techniques to map dynamic crosstalk among parenchymal cells, immune populations and ECM components and identify core therapeutic intervention nodes. Computational pharmacology simulation can replace single-pathway independent research to systematically predict CUR’s multi-target regulatory networks. Second, develop lesion-responsive intelligent delivery carriers tailored to organ-specific fibrotic pathology, such as MMP-2 activatable lung-targeted prodrugs and hyaluronic acid-modified hepatic stellate cell-specific liposomes. Combined with PET fluorescent tracing non-invasive imaging, real-time monitoring of CUR intralesional distribution can be realized. Third, rebuild standardized clinical research workflows: stratify patients via multi-omics molecular biomarkers to achieve precise molecular phenotyping, and deploy adaptive clinical trials that dynamically adjust CUR dosage regimens according to individual response. Artificial intelligence mining of real-world electronic medical records can shorten the cycle of clinical efficacy verification and lower trial costs. Only through systematic integrated innovation spanning mechanistic exploration, formulation optimization and clinical validation can CUR evolve from a multi-target laboratory candidate into a viable clinical therapeutic and functional food agent for diverse fibrotic disorders.

Conclusion

Fibrosis arises from sustained chronic inflammation, oxidative stress imbalance, disordered EMT and excessive ECM deposition, which collectively trigger irreversible structural damage and functional loss across visceral organs. As a GRAS-recognized food-derived polyphenol, CUR exerts broad-spectrum anti-fibrotic effects through shared core signaling axes alongside organ-specific regulatory pathways. Across PF, HF, MF and RF, CUR universally suppresses the pro-fibrotic TGF-β/Smad cascade and blocks NF-κB-mediated chronic inflammatory signaling while activating the Nrf2 antioxidant pathway to restrain myofibroblast activation; meanwhile, its organ-specific regulatory mechanisms exhibit prominent divergence. For HF, CUR primarily targets HSC-centered metabolic and epigenetic axes including Hh and CXCL12/CXCR4 signaling as well as the miR-29b/DNMT3b regulatory network; for PF, it intervenes in PERK-triggered endoplasmic reticulum stress and the miR-29a-3p/DNMT3A epigenetic axis to relieve scar formation; for MF, CUR relies on SIRT1 pathway modulation to restore cardiac redox homeostasis and balance MMP/TIMP-mediated matrix turnover; with regard to RF, it regulates tubular EMT via multiple cascades and remodels the gut-kidney axis to reduce circulating uremic toxin burden. Massive in vitro cellular and rodent in vivo evidence has consistently confirmed that CUR can reduce tissue collagen deposition, alleviate inflammatory cellular infiltration and slow fibrotic lesion progression in various disease models.

Nevertheless, multiple pharmacokinetic and formulation obstacles still impede the clinical transformation of CUR. Oral free CUR suffers from extremely low aqueous solubility, rapid gastrointestinal degradation and less than 1% oral bioavailability, making it unable to penetrate dense collagen-rich fibrotic scars to reach therapeutically effective local concentrations, and routine dietary CUR intake is far from sufficient to reverse mature established fibrosis. Up to now, a spectrum of delivery systems including liposomes, CP-LNPs, ligand-modified polymeric micelles, solid dispersions, SMEDDS and implantable hydrogels have been engineered to elevate CUR solubility and prolong in vivo circulation time, yet distinct disparities exist in their actual anti-fibrotic performance. Solid dispersions and untargeted SMEDDS merely optimize systemic pharmacokinetic profiles without scar penetration or cell-targeting capacity, and are thus only suitable for mild subclinical oxidative stress relief rather than progressive fibrotic lesions; conventional liposomes passively accumulate within hepatic immune cells and lack access to collagen-secreting HSCs and myofibroblasts, only exerting partial anti-inflammatory effects without reversing ECM overproduction; by contrast, organ-responsive ligand-conjugated micelles and renal dual-network hydrogels have obtained sufficient animal model validation to cross ECM barriers and selectively act on core profibrotic cells, carrying greater potential as targeted anti-fibrotic delivery vehicles. Even so, the vast majority of existing nanomedicine research only documents basic physicochemical indicators such as particle size and solubility, while lacking systematic in vivo evidence of CUR accumulation within fibrotic microenvironments and long-term biosafety evaluation.

Another core translational bottleneck originates from the inherent defects of conventional preclinical models and insufficient high-grade clinical data. Most current mechanistic research relies on immortalized cell lines and acute injury rodent models induced by BLM, CCl₄, UUO or pressure overload, which fail to replicate the multi-etiology, aging-related degeneration and multiple comorbidities characteristic of human chronic fibrosis. Animal trials generally adopt impractically high CUR dosages and short observation periods spanning several weeks, whereas human fibrotic disorders progress over decades. To date, no large-scale randomized controlled trials have proven that CUR or its optimized formulations can halt or reverse mature fibrotic lesions in human patients, and available clinical data are limited to surrogate biomarkers and short-term safety readouts without hard endpoints such as scar regression. Furthermore, CUR’s dual identity as food additive and potential therapeutic creates ambiguous regulatory positioning, as GRAS certification only validates its safety under dietary consumption rather than anti-fibrotic therapeutic efficacy, and the absence of unified industrial standards for CUR pharmaceutical preparations further obstructs standardized clinical trial design and new drug approval procedures.

Looking ahead, three core research directions need to be prioritized for subsequent CUR anti-fibrosis investigations. Researchers should first replace single-cell and acute rodent models with patient-derived organoids and organ-on-a-chip platforms combined with spatial multi-omics to reconstruct humanized fibrotic microenvironments, so as to dynamically analyze interactive networks among parenchymal cells, immune cells and ECM and offset the limitations of traditional experimental systems. Secondly, formulation research should shift its focus from simple solubility improvement to developing MMP, ROS and pH multi-responsive intelligent carriers such as inhalable microparticles for PF and HSC-targeted lipid nanoparticles, paired with non-invasive PET tracing technology; co-delivery systems combining CUR and tissue repair peptides also deserve further exploration to achieve synergistic anti-fibrotic effects. Third, clinical trial frameworks require comprehensive optimization via multi-omics-based molecular subtyping of fibrosis patients to build adaptive trial protocols, while unified CUR production and quality control standards should be established alongside long-term safety data collection from patients with hepatic or renal impairment. Only full-chain collaborative research covering mechanistic study, formulation development and clinical validation can ultimately advance CUR from laboratory candidate compounds into clinically applicable anti-fibrotic therapeutics and functional food raw materials.

Funding Statement

This work was supported by the Key Research and Development Project for Cadre Healthcare of Sichuan Provincial Health Commission (Sichuan Cadre Healthcare Research ZH2024-501).

Abbreviations

CUR, Curcumin; ECM, Extracellular matrix; GRAS, Generally Recognized as Safe; SMEDDS, Self-microemulsifying drug delivery systems; HF, Hepatic fibrosis; MF, Myocardial fibrosis; PF, Pulmonary fibrosis; RF, Renal fibrosis; TGF-β, Transforming growth factor-β; NF-κB, Nuclear factor-κB; MAPK, Mitogen-activated protein kinase; EMT, Epithelial-mesenchymal transition; Co I, Collagen type I; α-SMA, α-smooth muscle actin; MMP, Matrix metalloproteinase; IL, Interleukin; TNF-α, Tumor necrosis factor-α; JNK, c-Jun N-terminal kinase; uPA, urokinase-type plasminogen activator; uPAR, urokinase-type plasminogen activator receptor; CXCL, Chemokine (C-X-C motif) ligand; COX-2, Cyclooxygenase-2; AMPKα, AMP-activated protein kinase α; PPAR-γ, Peroxisome proliferator-activated receptor γ; PERK, PKR-like ER kinase; PKR, Double-stranded RNA-dependent protein kinase; DNMT3A, DNA methyltransferase 3A; COL1A1, Collagen type I Alpha 1 chain; FN-1, Fibronectin-1; HSCs, Hepatic stellate cells; Smad, Sma- and Mad-related protein; LOX-1, lectin-like oxidized low-density lipoprotein receptor-1; CTGF, Connective tissue growth factor; Tβ-RI, TGF-β receptor type I; Tβ-RII, TGF-β receptor type II; AGEs, Advanced glycosylation end products; AGE-R1, Advanced glycosylation end products-receptor 1; PGC-1α, PPAR-γ coactivator-1α; SOD-2, Superoxide dismutase-2; DLK1, delta-like homolog 1; VEGF, Vascular endothelial growth factor; VEGFR-2, Vascular endothelial growth factor receptor 2; PDGFR-β, platelet-derived growth factor receptor β; ERK, extracellular signal-regulated kinase; mTOR, mammalian target of rapamycin; FAK, focal adhesion kinase; RhoA, Ras homolog family member A; LEPR/Ob-R, leptin receptor; ROS, reactive oxygen species; GCL, glutamate-cysteine ligase; IRS, insulin receptor substrate; PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B; GLUT4, glucose transporter type 4; Hh, Hedgehog; Shh, Sonic Hedgehog; TLR, Toll-like receptor; MyD88, myeloid differentiation primary response 88; HMGB1, high-mobility group box 1; CBR, cannabinoid Receptors; CB₁R, cannabinoid receptor 1; CB₂R, cannabinoid receptor 2; PTEN, phosphatase and tensin homolog; MAT2B, methionine adenosyltransferase 2B; HIF-1α, hypoxia-inducible factor-1α; KCs, Kupffer cells; MCP-1, monocyte chemoattractant protein-1; CCL7, C-C motif chemokine ligand 7; NK cells, Natural killer cells; Bax, Bcl-2-associated X protein; CXCR4, C-X-C chemokine receptor type 4; CXCL12, C-X-C motif chemokine ligand 12; ZO-1, Zonula occludens-1; RAAS, renin-angiotensin-aldosterone system; Ang II, Angiotensin II; STZ, Streptozotocin; PKC, Protein kinase C; MDA, malondialdehyde; TIMP, tissue inhibitors of matrix metalloproteinases; SIRT1, Silent information regulator sirtuin 1; HK-2, human proximal tubular epithelial cell; PAI-1, plasminogen activator inhibitor-1; Nrf2, nuclear factor erythroid 2-related factor 2; Keap1, Kelch-like ECH-associated protein 1; HO-1, heme oxygenase-1; RGMb, Repulsive guidance molecule b; ADAMTS, A Disintegrin and Metalloproteinase with Thrombospondin Motifs; FSP-1, fibroblast-specific protein 1; SCFAs, short-chain fatty acids; LPS, Lipopolysaccharide; TMAO, trimethylamine N-oxide; NLRP3, NOD-like receptor pyrin domain-containing 3; CP-LNPs, Cholinized polymer-functionalized lipid nanoparticles; PEG, polyethylene glycol; GCS, gelatin-CUR-zinc dual-network hydrogel; Ac-SDKP, Ac-Ser-Asp-Lys-Pro; ALT, alanine transaminase; AST, aspartate transaminase; ALP, alkaline phosphatase; TBIL, total bilirubin; HA, hyaluronic acid; LN, laminin; PCIII, procollagen type III; Scr, serum creatinine; BUN, blood urea nitrogen; CCr, creatinine clearance; SBP, systolic blood pressure; MPO, myeloperoxidase; EPO, eosinophil peroxidase; NO, nitric oxide; IgE, Immunoglobulin E; BALF, bronchoalveolar lavage fluid; OVA, ovalbumin; BLM, Bleomycin; CCl₄, carbon tetrachloride; TAA, thioacetamide; ISO, isoproterenol; UUO, unilateral ureteral obstruction.

Data Sharing Statement

No new data were created or analyzed in this study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare no conflicts of interest.