Taming fatty liver: can taurine combat metabolic dysfunction in MASLD?

Abstract

Metabolic dysfunction associated with steatotic liver disease (MASLD) is the most prevalent chronic liver disease globally, significantly impacting human health and imposing substantial socioeconomic burdens. Characterized by excessive lipid accumulation in the liver, MASLD can progress to non-alcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC). Despite extensive research, the molecular mechanisms underlying MASLD remain incompletely understood, and no effective pharmacological treatments have been approved. This review explores the potential mechanisms of MASLD pathogenesis, early diagnostic approaches, and the promising role of taurine in mitigating MASLD progression via the gut-liver axis. As research advances, taurine may offer a novel therapeutic avenue, presenting new possibilities for effective clinical interventions in MASLD management.

Graphical Abstract

Introduction

A common discussion suggested Metabolic dysfunction associated with steatotic liver disease (MASLD) instead of the original name Non-alcoholic fatty liver disease (NAFLD) [1]. The prevalence of metabolic syndrome, obesity, and diabetes has significantly increased, contributing to a sharp rise in MASLD incidence, now affecting approximately one-quarter of the global population. Recent estimates suggest that MASLD impacts up to one billion individuals globally [2].

Currently, the “Multiple-hit” hypothesis is widely accepted as the mechanism underlying MASLD pathogenesis. This hypothesis encompasses hepatic lipid metabolism disorders, endoplasmic reticulum stress, insulin resistance, and gut microbiota dysbiosis. The concept of the gut-liver axis has gained prominence, highlighting the bidirectional exchange of nutrients and signals between the liver and gut via the portal vein and biliary system. Consequently, disruptions in gut microbiota, alterations in microbial metabolites, and impairment of the intestinal barrier can inflict damage on the liver. This review emphasizes the pivotal role of the gut-liver axis in the progression of MASLD.

Existing diagnostic methods for MASLD have several limitations: ultrasound cannot detect mild hepatic steatosis; 50%−80% of MASLD patients may have normal liver enzyme levels; and liver biopsy, the gold standard, involves significant sampling error [3]. To date, there are no clinically approved targeted therapies for MASLD, with disease management primarily relying on dietary and lifestyle modifications. However, significant advancements in early diagnostic techniques for MASLD have been made in the past fifteen years. Non-invasive blood tests like NIS4 can significantly reduce unnecessary liver biopsies in low-risk patients [4, 5]. The exploration of natural products offers a promising new direction for MASLD treatment due to their high sustainability, low side effects, and multiple therapeutic targets.

Taurine, an unconventional natural product, has garnered attention for its beneficial health properties and high availability. Recognized as a cytoprotective molecule, taurine maintains the normal electron transport chain, preserves glutathione stores, upregulates antioxidant responses, enhances membrane stability, reduces inflammation, and prevents calcium accumulation [6]. Numerous clinical trials have demonstrated taurine’s positive effects in mitigating conditions such as obesity [7] and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) [8]. This review comprehensively examines the physiological functions of taurine and its mechanisms in alleviating MASLD progression by modulating hepatocytes, the gut microenvironment, and the gut-liver axis.

Physiology of taurine

Biosynthesis and regulation of taurine

Taurine (2-aminoethanesulfonic acid) is a sulfur-containing amino acid and one of the most abundant amino acids in excitable tissues, constituting approximately 0.1% of total body weight [9]. Taurine has gained attention due to its roles in regulating cholesterol metabolism through bile acid levels, combating oxidative stress, and modulating the immune system [6]. It is now a common ingredient in many energy drinks [10].

In humans, taurine can be obtained from two primary sources: dietary intake and endogenous synthesis from certain amino acids, such as hypotaurine and cysteine. Cysteine, a byproduct of the metabolism of sulfur-containing amino acids (methionine and cysteine), is converted to cysteine sulfinic acid (CSA) by cysteine dioxygenase (CDO) [11]. The liver is the main site for taurine synthesis in the body. It has significantly higher CDO and cysteine sulfinic acid decarboxylase (CSD) activity compared to other tissues, primarily synthesizing taurine through the “cysteine sulfinic acid pathway”. In mammals, taurine synthesis involves the sequential actions of CDO and CSD, which catalyze the conversion of CSA to hypotaurine, which is then oxidized to taurine. Studies have shown that flavin-containing monooxygenase 1 (FMO1) also plays a role in converting hypotaurine to taurine in a NADPH or NADH-dependent manner [12].

Maintaining high taurine concentrations in tissues such as the retina, neutrophils, neurons, heart, and skeletal muscle depends on the sodium-dependent taurine transporter (TAUT) for uptake from the blood [13]. Dietary intake is another crucial source of taurine, with the gastrointestinal tract facilitating taurine absorption and enterohepatic recirculation. Taurine is essential for nutrient absorption and body composition because it conjugates with bile acids to form bile salts, which promote dietary fat absorption [14].

Taurine’s role in bile acid conjugation is crucial for its physiological functions, as it enhances bile acid solubility [14]. Conjugated bile acids, such as taurocholic acid (TCA), taurodeoxycholic acid (TDCA), taurochenodeoxycholic acid (TCDCA), taurolithocholic acid (TLCA), and tauroursodeoxycholic acid (TUDCA), increase their affinity for membrane receptors and nuclear receptors involved in metabolic regulation. These primary bile acids, synthesized in the liver, are transported through the biliary system to the small intestine, where they are deconjugated by gut bacteria possessing bile salt hydrolase (BSH) activity, such as Lactobacillus, Bifidobacterium, and Listeria. This process releases taurine, which plays significant roles in the gut [15].

In summary, taurine is a vital amino acid synthesized primarily in the liver and obtained through diet. It plays crucial roles in bile acid conjugation, nutrient absorption, and various physiological processes, making it an important molecule for maintaining health and combating diseases like MASLD.

Clinical applications of taurine

Extensive research has confirmed the beneficial effects of taurine on various human organ systems. Studies have demonstrated that taurine plays vital roles in the nervous, muscular, retinal, ovarian, immune, and cardiovascular systems [16–18]. The physiological benefits of taurine have been validated through in vitro cell experiments, in vivo animal studies, and Phase I and II clinical trials. Notably, taurine has unique advantages for the cardiovascular system, including blood pressure regulation, anti-inflammatory effects, and improved endothelial function, all of which contribute to a reduced risk of cardiovascular diseases [19].

Telomere length, closely associated with cellular longevity, is significantly influenced by taurine levels. Telomere shortening limits cellular proliferative capacity. Existing literature reports that the addition of telomerase inhibitors induces cellular senescence in the hepatocyte microenvironment by triggering a sustained DNA damage response (DDR). Although senescence in hepatic stellate cells (HSCs) can suppress their pro-fibrotic phenotype, the predominant research focus has shifted to senescent hepatocytes exhibiting the senescence-associated secretory phenotype (SASP). These SASP-positive hepatocytes secrete substantial quantities of pro-inflammatory cytokines (e.g., IL-6, IL-1β, TNF-α), chemokines, and pro-fibrogenic factors (e.g., TGF-β, CTGF, PAI-1). This secretory profile constitutes a central driver in the progression of NAFLD to NASH and fibrosis. The etiopathogenesis of non-alcoholic fatty liver disease (NAFLD) is currently mainly explained within the framework of the “multiple-hit” hypothesis. This model includes progressive stages of injury: First hit: Insulin resistance-induced lipid accumulation in hepatocytes (steatosis); Second hit: Oxidative stress and lipid peroxidation-mediated hepatocyte injury, which promotes inflammatory response and fibrogenesis; Third hit: A synergistic injury network that evolves on the basis of the second hit, encompassing multiple pathological factors such as lipotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress, adipose tissue-derived inflammatory factors, and gut microbiota-derived endotoxins.

Taurine, a widely distributed amino acid, has been demonstrated to confer multifaceted benefits for liver health and metabolic diseases, including alleviating hepatic steatosis, improving the gut microenvironment, and reducing oxidative stress. Moreover, taurine may promote cell health and delay cellular senescence through multiple pathways, thereby providing comprehensive support for liver health. A correlation has been observed between hepatic telomere length and plasma taurine levels in mice [20]. Moreover, a randomized controlled trial evaluated the effects of acute taurine supplementation (3 g and 6 g) on lipid oxidation in healthy young men following moderate-intensity exercise in a fasted state. Results indicated a significant increase in lipid oxidation [21]. Taurine may influence lipid oxidation by activating adenylate cyclase, thereby directly stimulating cyclic adenosine monophosphate (cAMP) production or by increasing catecholamine secretion [22].

Overall, taurine demonstrates substantial potential in clinical applications across various health domains, particularly in cardiovascular health, anti-aging, neurological protection, and metabolic regulation. Its diverse physiological effects and the growing body of evidence support taurine as a valuable therapeutic agent for multiple conditions.

Gut-liver axis and MASLD

Although many mechanisms contribute to MASLD, recent research has centered on the gut–liver axis, which refers to the two-way movement of nutrients, microbial products, and bile acids between the intestine and the liver through the portal vein and the biliary tract. Interactions among the gut microbiota, the immune system, and microbe-derived metabolites are now seen as major drivers of liver metabolism, inflammation, and detoxification in chronic liver disease [23]. In this section, we will explore how the liver, gut, and gut microbiota interact to promote the development and progression of MASLD.

Intestinal barrier integrity and endotoxin translocation

The intestinal barrier—comprising the mucus layer, epithelial tight junctions, immune defenses, and chemical/biological shields—prevents bacteria and toxins from entering the portal blood and reaching the liver. When this barrier is weakened, microbial products cross the epithelium and travel to the liver, sustaining low-grade inflammation and injury [24]. The intestinal barrier comprises mechanical, immune, chemical, and biological layers that operate in concert to preserve mucosal integrity and protect the liver from microbial products [25]. Within the mechanical layer, the mucus blanket and the epithelial sheet form the primary seal: the mucus prevents direct bacterial contact with intestinal epithelial cells and contains mucins such as MUC2, antimicrobial peptides, and secretory IgA, while the epithelial cells are joined by tight junctions, adherens junctions, and desmosomes that control paracellular flux [26]. When tight-junction structure or regulation is compromised, permeability rises; in clinical and experimental settings, greater permeability associates closely with the severity of NAFLD/MASLD, underscoring that the coordinated network of mucus, antimicrobial peptides, and tight-junction proteins is essential for barrier function [27].

Obesity is thought to give rise to increased intestinal permeability, which results in the leakage of lipopolysaccharide (LPS), an endotoxin released by gram-negative bacteria, into the blood and leads to metabolic endotoxemia. Metabolic endotoxemia, an important obesogenic mechanism, then triggers a signaling cascade leading to the activation of various proinflammatory pathways, increases oxidative stress via LPS binding to its pattern recognition receptor Toll-like receptor 4 (TLR4), and ultimately drives systemic low-grade inflammation and insulin resistance [28].

Microbial metabolites and epigenetics

Microbial metabolites shape MASLD by steering innate immunity, especially macrophage behavior. Bile acids (BAs) that signal through TGR5 and FXR tend to reduce NF-κB activity in macrophages and increase IL-10, which shifts cells from M1-like to M2-like states and lowers inflammatory tone [29]. In contrast, ox-LDL, palmitate, and other saturated fatty acids can activate TLR2/4 and the NLRP3 inflammasome, which promotes IL-1β production and an M1-like profile. BA species differ in their immune effects. DCA and CDCA can act as metabolic danger signals and activate both signals 1 and 2 of the NLRP3 inflammasome, which increases IL-1β release, whereas LCA can suppress NLRP3 via TGR5 signaling and can reduce macrophage uptake of oxidized LDL [30].

These phenotypes track with cellular metabolism. M1-like macrophages disrupt the TCA cycle, accumulate itaconate, and depend on glycolysis, which supports ROS and IL-1β production. M2-like macrophages rely on oxidative phosphorylation (OXPHOS) and support tissue repair. The SCFA butyrate promotes OXPHOS and lipid metabolism and thereby favors M2 differentiation [31]. Glutamine and α-ketoglutarate support the TCA cycle and ETC and reinforce M2 programs that help repair liver injury [30]. In intestinal macrophages, butyrate can reduce glycolysis and mTOR activity, which softens inflammatory responses [32]. Itaconate and related derivatives can activate Nrf2 and limit ROS–MAPK–NF-κB signaling and pyroptosis, which reduces myeloid infiltration and downstream cytotoxic T-cell skewing [33]. Acetate can enhance glycolysis, HIF-1α, and IL-1β, sometimes in an NLRP3-dependent manner, whereas butyrate can also engage HIF-1α through HDAC inhibition, showing that SCFA effects are context dependent [34]. Consistent with these patterns, sodium butyrate lowers LPS-induced inflammation in intestinal macrophages and PBMCs through GPR43/β-arrestin-2/NF-κB signaling [35]. Colonic microbes can trigger NLRP6-mediated caspase-1 activation and IL-18 release, and SCFAs acting at GPR43 and GPR109A help maintain homeostatic IL-18 levels that prevent excessive intestinal and hepatic inflammation [36].

Microbial metabolites also influence adaptive immunity. LCA derivatives such as 3-oxoLCA bind RORγt and dampen Th17 cells [31, 37], and LCA can reduce Th1 cytokines IFN-γ and TNF-α in human and mouse CD4⁺ T cells [37]. SCFAs modulate T-cell metabolism. They increase OXPHOS and mitochondrial mass in CD8⁺ T cells; butyrate promotes fatty-acid uptake and oxidation and favors OXPHOS through fatty-acid catabolism and glutamine use; under stress, acetate expands the acetyl-CoA pool via the TCA cycle and ATP citrate lyase and supports protein acetylation such as GAPDH in memory CD8⁺ T cells [31]. Propionate promotes Treg production of IL-10 through GPR43 and reduces IL-17 from intestinal γδ T cells through HDAC-dependent mechanisms [33]. These immune shifts help explain how metabolite profiles translate into different inflammatory outcomes in MASLD.

Microbial metabolites also remodel epigenetic regulation, which reprograms metabolism and inflammation. Epigenetic mechanisms include DNA methylation, histone modifications, non-coding RNAs, and chromatin remodeling [38]. Several microbial products provide substrates or signals that change enzyme activity and gene expression in intestinal epithelial cells and the liver, which can propagate along the gut–liver axis and disturb hepatic metabolism [39]. Consequently, epigenetics is increasingly recognized as a potential mechanism in the development of liver diseases.

Gut microbiota metabolites can influence DNA methylation, thereby impacting glucose and lipid metabolism and affecting the progression of MASLD. Folate and B-vitamins (for example B2 and B12) drive one-carbon metabolism to generate S-adenosyl-methionine (SAM) [40], and can directly channel dietary methionine into SAM [41], which supplies methyl groups for DNA and histone methylation. Succinate and fumarate, two TCA intermediates, can inhibit TET and jmjC demethylases; microbial H₂S can induce H3K4me2 at selected promoters; NO can promote S-nitrosylation of Argonaute proteins ALG-1 and AGO2, which alters methyltransferase activity and thereby changes gene expression [40].

Histone modifications are also targeted. SCFAs inhibit HDAC activity and can increase chromatin accessibility and target-gene expression. Gut microbes can enhance Jmjd3/Kdm6b activity in response to Tlr2 and thereby adjust H3K27 methylation states; they can also influence deacetylation by changing HDAC activity [41]. Some microbes produce IP3 and phytic acid, which increase HDAC3 expression and counterbalance SCFA-mediated HDAC inhibition [42]. Bacteroides can induce histone deacetylation through TGF-β1, and SCFAs can be metabolized to Ac-CoA or R-CoA to acylate histones directly or to serve as acyl donors for HATs [40].

Non-coding RNAs are another layer of control. They include miRNAs, snRNAs, and piRNAs among small RNAs, as well as lncRNAs and circRNAs [43]. Microbiota depletion with antibiotics for six weeks reduces intestinal miRNA expression in rats, and SCFAs such as acetate and butyrate can improve obesity and metabolic syndrome by regulating miR-378 A/YY1 promoter methylation; tryptophan-derived metabolites can improve insulin resistance by controlling miR-181 in white adipocytes; the microbiota can also regulate circulating miR-122-5p, which affects insulin secretion and signaling in patients with type 2 diabetes and influences white-adipose-tissue browning [38] (Fig. 1).

Fig. 1.

The role of epigenetic modifications in MASLD

Immune modulation in the liver

The liver comprises an intricate network of innate immune cells and the adaptive immune system. The innate immune cells include neutrophils, monocytes, Kupffer cells (KCs), dendritic cells (DCs), natural killer (NK) cells, innate lymphoid cells (ILCs), invariant NKT (iNKT) cells, and mucosal-associated invariant T (MAIT) cells. The adaptive immune system encompasses lymphocytes, including conventional T cells (CD4, CD8, and γδ T cells), unconventional regulatory T cells (NKT and MAIT cells), and B cells. Innate immune cells are primarily responsible for the onset of liver injury, while adaptive immune cells play a crucial role in chronic inflammation due to sustained liver injury [44].

Macrophages, a key component of the innate immune system, include resident KCs, monocyte-derived macrophages (MoMFs), and capsular macrophages in the liver. Kupffer cells constitute the majority (95%) of liver macrophages [45]. In MASLD, KCs are a major source of cytokines and chemokines. The role of macrophages in liver inflammation, their programmed death, and the crosstalk between hepatic macrophages and hepatocytes are pivotal in the pathological progression of MASLD.

In MASLD, KCs are activated first, releasing inflammatory factors that impact liver inflammation. KC activation occurs through several pathways: gut-derived endotoxins like lipopolysaccharide (LPS) enter circulation via Toll-like receptors (TLRs) due to increased gut permeability; damage-associated molecular patterns (DAMPs) and histidine-rich glycoproteins (HRG) related to hepatocyte injury; free fatty acids (FFAs) through TLRs; leptin via leptin receptors (LEPR); and cholesterol and its metabolites via CD36 and scavenger receptor A (SRA). Activated KCs secrete pro-inflammatory cytokines such as tumor necrosis factor (TNF), IL-1β, and IL-6, recruiting neutrophils and circulating monocytes through the CC-chemokine ligand 2 (CCL2)-CC-chemokine receptor 2 (CCR2) interaction. Monocytes differentiate into pro-inflammatory macrophages, amplifying liver inflammation, and stimulating hepatic stellate cells (HSCs) through transforming growth factor-β (TGF-β), promoting their conversion into activated myofibroblasts and extracellular matrix deposition. KCs also downregulate peroxisome proliferator-activated receptor α (PPARα) in hepatocytes by secreting IL-1β, promoting steatosis and insulin resistance. Additionally, KCs promote hepatocyte apoptosis and inflammation progression by phagocytosing apoptotic bodies and producing TNF, TRAIL, and Fas ligand [46].

The interaction between hepatic macrophages and other liver cells plays a crucial role in MASLD progression. Metabolic reprogramming is emerging as a key regulator of hepatic macrophage polarization. M1 macrophages mainly rely on aerobic glycolysis, which is also called the Warburg effect, whereas M2 macrophages that possess an intact tricarboxylic acid (TCA) cycle and electron transport chain (ETC) can produce adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). They can acquire different activation states in response to endogenous danger stimuli and then promote either inflammation (M1) or tissue repair (M2) [30]. Adaptive immunity also plays a significant role in MASLD/NASH patients. Existing research indicates that adaptive immunity participates in MASLD progression, but the specific mechanisms require further detailed investigation (Fig. 2).

Fig. 2.

The roles of the immunocytes in MASLD

Mechanisms of taurine in alleviating MASLD

The initial stage of MASLD progression is simple steatosis, marked by intracellular lipid accumulation, which can often be reversed with lifestyle changes. However, the progression to NASH is driven by increased endoplasmic reticulum stress, mitochondrial dysfunction, oxidative stress, and insulin resistance associated with metabolic syndrome, leading to hepatocyte injury and inflammation. Interestingly, taurine shows potential protective effects in these key pathological mechanisms, such as its powerful antioxidant properties and the ability to stabilize endoplasmic reticulum function. Chronic hepatocyte damage, persistent inflammatory environments, and excessive regulated cell death (RCD) promote fibrotic tissue deposition, signaling the onset of liver fibrosis [47].Some relevant studies suggest that supplementing taurine may help inhibit this fibrosis process.

As previously discussed, in this cascade of pathological events ranging from steatosis to inflammation and fibrosis, the dysregulation of the gut-liver axis plays a core role, and taurine has also been found to actively regulate the gut-liver axis. Changes in gut microbiota composition can directly affect the concentration and composition of microbial metabolites, influencing gene expression through epigenetic modifications such as DNA methylation. This, in turn, affects lipid metabolism and inflammatory responses. Additionally, gut bacteria produce specific metabolites like SCFAs that regulate host gene expression and immune function, thereby impacting MASLD progression. Dysbiosis can impair gut barrier function, allowing endotoxins and metabolites to enter the bloodstream, leading to chronic low-grade inflammation and liver injury. It is of concern that taurine has been proven to improve the composition of the intestinal bacteria, enhance intestinal barrier function and reduce endotoxin translocation, which provides a mechanism basis for its intervention in the gut-liver axis link of MASLD.

Understanding these mechanisms not only enhances our comprehension of the disease but also helps identify key molecular targets in MASLD progression. This knowledge is critical for explaining how taurine can modulate these targets, such as hyperactive signaling pathways and abnormally expressed proteins, to inhibit the progression of MASLD to NASH, fibrosis, cirrhosis, or even hepatocellular carcinoma. In the following sections, we will focus on how taurine intervenes in the various stages of MASLD to halt disease progression (Fig. 3).

Fig. 3.

Taurine and the mechanism of progression in MASLD

Taurine and lipid metabolism

The liver plays a critical role in maintaining cholesterol homeostasis through uptake, synthesis, and secretion. Cholesterol is synthesized in the liver by HMG-CoA reductase, taken up from peripheral tissues via high-density lipoprotein receptors, and absorbed from the intestine through Niemann-Pick C1-Like 1 (NPC1L1) transporters [48]. Cholesterol is cleared from hepatocytes by converting it to bile acids and secreting it into the gallbladder. The liver contains all the enzymes necessary for this metabolic pathway, including the rate-limiting enzyme cytochrome P450 family member 7A1 (CYP7A1) [49].

The increase in lipid content in MASLD involves five main processes:

1. Dietary intake: The digestion and absorption of dietary triglycerides (TG) are mediated by bile acids and specific bile acid receptors like the farnesoid X receptor (FXR). The transport of dietary TGs is regulated by PPARγ.

2. De novo lipogenesis (DNL): The conversion of non-fatty acid substrates (e.g., glucose, lactate, and amino acids) into fatty acids (FAs) in the liver involves several enzymes, including Acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD1). DNL is a key pathway promoting lipid accumulation, increasing through the activation of transcription factors like sterol regulatory element-binding protein-1 (SREBP-1), carbohydrate-responsive element-binding protein (ChREBP), and PPAR-γ. SREBP-1, mainly existing as SREBP-1c, is regulated by insulin and involved in DNL activation. IR activates SREBP-1c by downregulating IRS-2, promoting hepatic DNL. Elevated glucose levels activate ChREBP, regulating the expression of ACC and FAS, thus promoting hepatic DNL [50].

3. Increased lipolysis: The breakdown of TGs into FFAs and glycerol is facilitated by patatin-like phospholipase domain-containing 3 gene (PNPLA3). Increased lipolysis, without effective FFA transport or oxidative metabolism, leads to hepatic steatosis.

4. Reduced β-oxidation: β-oxidation primarily occurs in mitochondria and peroxisomes, being the main pathway for FA metabolism. PPARα activation induces the transcription of β-oxidation-related genes, reducing hepatic lipid levels.

5. Reduced lipid transport: Cholesterol and TGs are transported from the liver to extrahepatic tissues as very low-density lipoproteins (VLDL). Reduced transport rates lead to TG accumulation in the liver.

In MASLD, increased hepatic cholesterol synthesis and uptake, coupled with reduced cholesterol clearance, result in elevated hepatic cholesterol levels and widespread cholesterol imbalance. Taurine has been shown to modulate hepatic cholesterol metabolism, which is crucial in NASH related to lipid metabolism.

Taurine enhances fecal bile acid excretion in hypercholesterolemic rat, ssuggesting reduced hepatic cholesterol levels might be related to increased bile acid excretion [51]. In vitro studies confirm taurine significantly induces CYP7A1 expression in HepG2 cells in a cholesterol-dependent, time- and dose-dependent manner [52]. The related signaling pathways are gradually being elucidated. Fibroblast growth factor 21 (FGF21), secreted by the liver, regulates fat and glucose metabolism. FGF21 inhibits CYP7A1 gene expression by inducing ERK phosphorylation [53]. Long-term taurine feeding in mice increases CYP7A1 expression and reduces plasma cholesterol levels through the FGF21-ERK signaling pathway by decreasing hepatic FGF21 mRNA levels, inhibiting downstream ERK phosphorylation, and relieving ERK’s inhibition on Hepatocyte nuclear factor 4α (HNF4α) dimer formation [54]. HNF4α transcriptional activity requires both nuclear localization and homodimer formation. Upon inhibition relief, CYP7A1 transcription increases, leading to reduced hepatic cholesterol levels.

Taurine positively correlates with SIRT1 expression in a concentration-dependent manner. It upregulates SIRT1 (sirtuin 1), promoting deacetylation, enhancing mRNA and protein levels of downstream molecules PPAR-α, LXR-β, PGC-1, and SREBP-1, while reducing PGC-1α expression, thereby regulating lipid metabolism genes to exert lipid-lowering effects [55]. As a nuclear receptor, LXR acts as a cholesterol sensor, promoting cholesterol transport and excretion and inhibiting cholesterol synthesis, thus protecting hepatocytes from cholesterol overload damage. Taurine increases AMPK Thr172 phosphorylation in steatotic HepG2 cells, possibly due to elevated phosphorylation levels of the upstream kinase LKB1-Ser428 in the livers of high-fat diet rats [56]. Activated AMPK enhances deacetylase activity, removing acetyl groups from SREBP-1c lysines 289 and 309, directly inhibiting SREBP-1c [57]. Sterol regulatory element-binding proteins (SREBPs) anchor to the ER membrane with SCAP. As SREBPs’ escort and sterol sensor, SCAP escorts SREBP from the ER to the Golgi when cellular cholesterol is depleted. In the Golgi, two proteases, S1P and S2P, cleave SREBP to generate the NH2-terminal bHLHZip domain, nSREBP. It translocates to the nucleus, where it binds to non-palindromic sterol response elements (SREs) in multiple target gene promoters/enhancers, activating transcription. Under sterol-depleted conditions, SREBP-SCAP preferentially binds the Insig2a subtype in the liver, retaining it in the ER membrane, thus preventing nSREBP-1c formation and reducing SREBP-1c-regulated gene expression. Taurine-induced SREBP-1c delayed nuclear translocation might be achieved through Insig-2a gene induction. Taurine stimulates HepG2 cells to express Insig-2a mRNA, retaining the INSIG2-SCAP-SREBP-1c complex in the ER, reducing the expression of hepatic lipogenic genes like Fas and SCD-1 regulated by SREBP1c [58].

Taurine and anti-inflammatory effects

Taurine and oxidative stress

MASLD patients exhibit mitochondrial ultrastructural damage, reduced activity of respiratory chain complexes, and impaired ATP synthesis.

Accumulation of ROS in hepatocytes impairs pathways involved in MASLD development, such as lipid metabolism, insulin signaling, inflammation, and apoptosis [59]. Oxidative stress inhibits insulin signaling through the activation of IKKβ and JNK inhibitors [60]. PPAR-α in peroxisomes regulates three interconnected hepatic fatty acid oxidation systems: mitochondrial and peroxisomal β-oxidation and microsomal ω-oxidation. Sustained PPARα activation alleviates MASLD by enhancing FAO and reducing ROS levels. However, excessive PPARα activation increases H₂O₂ levels, leading to inflammation [61].

Taurine, a classic free radical scavenger, shows significant scavenging effects on peroxyl, nitric oxide, and superoxide donors, playing a vital role in maintaining cellular redox balance. Taurine reduces lipid peroxidation (LPO) products, protecting cells from tissue damage [62]. Taurine protects hepatocytes and enhances hepatic antioxidant capacity in both steatotic LO2 cells in vitro and FLHS animal models. Increased levels of oxidative stress markers such as malondialdehyde (MDA) and oxidized glutathione (GSSG) in the livers of rats fed a high-fat diet, along with decreased levels of reduced glutathione (GSH) and superoxide dismutase(SOD) activity, confirm the role of oxidative stress in fatty liver progression [63].

The Keap1/Nrf2 pathway is the primary protective response against oxidative stress. In cultured hepatocytes, taurine binds to Keap1, releasing Nrf2 from Keap1-mediated stress inhibition, allowing Nrf2 to translocate to the nucleus and activate antioxidant transcription programs, increasing the production of antioxidant enzymes like SOD, glutathione peroxidase (GPx), and glutathione-S-transferase (GST) to scavenge ROS and reduce oxidative stress [64].

Research indicates that hepatocyte mitochondrial damage is induced by various factors in fatty liver, a fundamental aspect of MASLD development [65]. Oxidative stress, often originating from mitochondrial dysfunction, plays a significant role in the progression from fatty liver to steatohepatitis. As an antioxidant, taurine potentially inhibits excessive oxidant production in mitochondria and maintains mitochondrial quantity and function. Taurine maintains mitochondrial dynamics balance by upregulating the expression of mitochondrial fusion proteins Mfn1, Mfn2, and OPA1 while downregulating the expression of mitochondrial fission proteins FIS1 and Drp1 [66]. The PINK1/Parkin pathway is a classic mitochondrial autophagy pathway. PTEN-induced putative kinase 1(PINK1) controls mitochondrial quality, protecting cells from oxidative stress [67]. Reports indicate that taurine increases PPARγ expression in arsenic-induced pancreatic cells and INS-1 cells in rats, significantly enhancing PINK1 expression, promoting mitochondrial autophagy through the PINK1/Parkin pathway, and reducing ROS production [68]. Literature suggests taurine regulates PINK1/Parkin pathway-related factors to resist oxidative stress in fatty liver cell models in vitro [66].

Dietary taurine supplementation may protect mitochondria and enhance aerobic lipid metabolism in the liver. Taurine activates the AMPK/SIRT1 signaling pathway, promoting mitochondrial β-oxidation of fatty acids. Activated SIRT1 and AMPK increase CPT-1 transcription and expression on the mitochondrial outer membrane, facilitating FFA entry into mitochondria [69]. Taurine upregulates PGC-1α and PGC-1α target genes Nrf1 (nuclear factor E2-related factor 1), Nrf2 (nuclear factor E2-related factor 2), and Tfam (mitochondrial transcription factor A) in steatotic hepatocytes [66]. Known studies indicate that NRF1 plays a key role in regulating nuclear genes encoding mitochondrial proteins, and TFAM initiates mitochondrial DNA (mtDNA) transcription and replication [70]. PGC-1α, as the “master regulator” of mitochondrial biogenesis, upregulates downstream genes NRF1 and TFAM, stabilizing mitochondrial structure and function in damaged cells, achieving antioxidant stress effects [71].

Literature emphasizes the role of taurine modification loss in mitochondrial diseases and establishes a link between taurine modification and mammalian mitochondrial translation optimization 1 (MTO1). Taurine post-transcriptionally modifies the wobble position of uridine in mitochondrial tRNA(Leu(UUR)) anticodon, critical for proper expression of mitochondrial-encoded proteins [72]. Although direct evidence linking taurine modification of mitochondrial tRNA to oxidative stress alleviation is lacking, taurine’s potential antioxidant mechanisms warrant further exploration.

Taurine and insulin resistance

Insulin resistance (IR) is a physiological condition involved in MASLD where cells fail to respond appropriately to insulin, impairing glucose uptake and metabolism [61]. IR leads to hepatic lipid metabolism disorders, particularly affecting fatty acid β-oxidation, DNL and VLDL synthesis [73]. Metabolic crosstalk between adipose tissue and the liver is evident, with adiponectin, IL-6, and other peptides released by adipose tissue exerting protective and pro-inflammatory effects in the liver. Dipeptidyl peptidase-4 (DPP-4) can synergize with plasma factor Xa to stimulate inflammatory macrophages in visceral adipose tissue, promoting IR [74].

In vivo experiments in mice demonstrate that taurine effectively ameliorates FFA-induced hepatic IR, potentially by reducing oxidative stress markers such as hepatic MDA and blocking the activation of the JNK1 pathway [75]. Taurine improves IR and subsequently ameliorates hyperglycemia and dyslipidemia in mice by reducing leptin secretion [76]. Clinical randomized trials show that taurine supplementation. combined with a low-calorie diet, significantly reduces serum insulin, malondialdehyde, TNF, and hs-CRP levels in diabetic patients, indicating taurine’s potential in improving IR and exerting anti-inflammatory effects [77]. The antidiabetic mechanisms of taurine are multifaceted. Supplementation in drinking water promotes β-cell proliferation, counteracts streptozotocin-induced upregulation of antioxidant genes (Sod1, Sod2, CAT, and Gpx1), downregulation of pancreatic islet expansion genes (Ngn3 and Itgb1), and enhances α-cell transdifferentiation to β-cells in islets. This correlates with nonmetabolic increases in cytoplasmic calcium concentrations in pancreatic α-cells, suggesting taurine’s potential antidiabetic effects through intracellular and extracellular signal regulation [78].

Identifying key microbial-derived metabolites and their host targets, rather than focusing solely on gut microbiota changes, is crucial. Taurine can participate in the gut-liver axis either directly or as metabolites, improving hepatic IR, reducing excessive hepatic fat infiltration and inflammation, and countering the progression of fatty liver to NASH. TUDCA treatment in mice lowers fasting hyperglycemia and hyperinsulinemia, showing significantly better insulin sensitivity and amelioration of HFD-induced obesity and IR [79]. In HFD-induced obese mice, taurine and betaine supplementation improve hepatic steatosis and restore insulin sensitivity. In taurine-supplemented HepG2 cells, fatty acid synthase (FASN)expression is downregulated [80]. Insulin clearance is higher in TUDCA-treated aged mice, potentially due to increased hepatic insulin-degrading enzyme (IDE) gene and protein expression, though the exact mechanism requires further research [81]. Penthorum chinense Pursh extract increases the concentration of conjugated bile acids like T-βMCA, TCDCA, and TUDCA in the gut by reducing the abundance of BSH bacteria, alleviating hepatic IR through the FXR-FGF15 axis [82]. Diammonium glycyrrhizinate supplementation in mice lowers BSH-enriched bacteria, increasing taurine-conjugated BAs, inhibiting ileal FXR-FGF15 feedback signaling, suppressing CYP7A1 expression, altering the BA profile, and improving metabolism, including lowering blood glucose and insulin levels, enhancing insulin sensitivity, reducing hepatic steatosis, and resisting weight gain [83]. Inhibition of gut L-cells FXR and FXR in a glycolysis-dependent manner promotes GLP-1 production and secretion, potentially benefiting IR improvement and MASLD relief [84]. This indirectly supports taurine supplementation’s feasibility in increasing taurine-conjugated bile acid concentrations and inhibiting the FXR-FGF15 axis to improve IR and metabolism. Taurine or taurine-conjugated bile acids as direct FXR antagonists warrant further exploration for their underlying mechanisms.

Taurine and anti-inflammatory effects on immune cells

The positive feedback loop between immune cells and inflammatory cytokines further promotes NASH progression, making the pro-inflammatory role of immune cells a critical area of focus. In atherosclerosis mouse models, continuous high-fat feeding exacerbates hepatic steatosis. Treatment with diacetyldiazenium diolate (DIZE) significantly increased the expression of chitinase-like protein 4 (YM2) and cysteine sulfinic acid decarboxylase (CSAD) in the liver [85]. CSAD is an enzyme involved in taurine biosynthesis, converting cysteine sulfinic acid to hypotaurine and carbon dioxide [86]. YM1, a protein with high sequence similarity to YM2, is considered an M2 macrophage marker in mice [87]. Dietary taurine supplementation can prevent obesity development and regulate macrophage polarization towards the anti-inflammatory M2 phenotype, thereby inhibiting inflammation and improving insulin sensitivity [88]. It is worth investigating how elevated intracellular taurine upregulates macrophage conversion to the M2 subtype or how M2 macrophages upregulate taurine synthesis to achieve anti-inflammatory effects.

In neutrophils, taurine reacts directly with hypochlorous acid (HOCl) to form N-chlorotaurine, effectively scavenging HOCl [89]. Following an oxidative burst, neutrophils undergo apoptosis and release TauCl at the site of inflammation, where dendritic cells and macrophages infiltrate. The production and release of TauCl seem to play a crucial role in protecting phagocytes from self-inflicted oxidative damage under inflammatory conditions by inhibiting further ROS and HOCl₂ production [90].

Taurine’s role in modulating immune responses extends to various cell types and mechanisms, highlighting its potential as an anti-inflammatory agent in MASLD and NASH. Understanding these processes can provide valuable insights into therapeutic strategies aimed at reducing inflammation and preventing disease progression.

Taurine and the gut-liver axis

The relationship between taurine and gut microbiota has gained significant attention in recent years. In healthy mice, dietary taurine supplementation alters the gut microbiome and affects its metabolism, increasing the production of SCFAs [91]. In mice treated with 5-fluorouracil (5FU), taurine restores gut microbiota balance and increases SCFA production [92]. Taurine has been identified as a major differential metabolite in serum from patients with gestational diabetes and neonatal meconium, suggesting a potential link between taurine and neonatal gut microbiota [93]. In immunosuppressed mice, taurine supplementation reverses the reduction in Lachnospiraceae and Ruminococcaceae and improves immune cell counts in Peyer’s patches, positively impacting gut homeostasis [94]. A recent report described how taurine supplementation trains the gut microbiota, leading to the expansion of taurine-utilizing groups and remodeling microbial functions. These microbes convert taurine into ammonia, acetate, and sulfide, the latter inhibiting pathogenic aerobic respiration and enhancing colonization resistance [95].

Taurine enhances gut barrier function. A study on total parenteral nutrition (TPN) showed that taurine improves gut mucosal thickness and villus height [96]. Taurine increases the number and function of goblet cells, improving the gut mucosal barrier during nematode infection and acute mucosal inflammation induced by LPS [97]. Taurine stimulates epithelial cell growth and translation by altering gene expression in purified epithelial cells. It reduces gut permeability and increases the expression of tight junction proteins in intestinal epithelial cells (Caco-2 cell monolayers), enhancing intestinal integrity and reducing gut leakage and inflammation [98]. Moreover, increased taurine in the intestines of C. elegans improves age-related dysfunctions like obesity and gut leakage.

Taurine supplementation leads to an increase in sulfur-producing bacteria. Taurine-respiring bacteria (e.g., Bilophila wadsworthia) convert dietary taurine into H2S, while 7α-dehydroxylating bacteria (e.g., Clostridium scindens) convert taurine-conjugated bile acids into deoxycholic acid [99]. Studies on healthy mice show that taurine increases the relative abundance of Actinobacteria and Proteobacteria, with Bifidobacterium and Lactobacillus being the most significant genera. Lachnospiraceae and Ruminococcaceae are identified as biomarkers in the taurine group, indicating increased taurine-conjugated bile acids, which undergo deconjugation by BSH and 7α-dehydroxylation [100]. Bilophila, an obligate anaerobic sulfate-reducing bacterium, uses taurine as a growth substrate, containing both BSH and taurine aminotransferase, catalyzing the first step in taurine catabolism [101]. Studies show taurine supplementation promotes the expansion of Deltaproteobacteria, converting taurine or sulfate into sulfite and ultimately into sulfide through dissimilatory sulfite reductase (dsr), enhancing resistance against pathogens like Klebsiella pneumonia [95].

Taurine supplementation can protect gut microbiota from antibiotic exposure and reverse its effects, restoring lactobacilli abundance and reversing anaerobic environment disruption caused by rodent infections [101]. Taurine-derived sulfides inhibit cytochrome oxidase activity, limiting pathogen aerobic respiration substrates, altering the gut environment by enriching Proteobacteria. Taurine also alleviates Clostridium rodentium infection by reducing colonic crypt hyperplasia, mitigating infection symptoms [95] (Fig. 4).

Fig. 4.

Taurine and the gut-liver axis in MASLD

Taurine and regulated cell death (RCD)

Hepatocyte death is a critical event in the progression of liver diseases, as the resultant inflammation leads to liver fibrosis, promoting the irreversible progression of MASLD. Consequently, regulated cell death (RCD) has been proposed to guide the assessment of hepatocyte injury severity and prognosis. RCD includes various forms such as apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis, each exhibiting distinct characteristics while sharing similarities, resulting in considerable overlap and crosstalk [100]. In response to lipid metabolism disorders, inflammation, ER stress, and mitochondrial dysfunction, hepatocytes activate RCD regulatory mechanisms to remove necrotic material, mitigate fibrosis, and maintain hepatic homeostasis [102]. However, the intricate interactions among different RCD forms can lead to the activation of alternative pathways when one is inhibited, undermining the liver’s benefit from RCD. Thus, precisely targeting therapeutic interventions to specific pathways is crucial. Recent studies have focused on taurine’s effects on RCD-related signaling pathways to protect normal hepatocyte function. Here, we summarize these findings.

Taurine and autophagy

Autophagy is a cellular degradation process that removes damaged organelles and proteins, playing a protective role in liver diseases. Taurine enhances autophagy by upregulating autophagy-related genes (Atg) and promoting the formation of autophagosomes. This process is mediated through the activation of AMPK and inhibition of mTOR pathways, which are critical regulators of autophagyn [103]. Increasing evidence shows that hepatocyte autophagy has a dual role in MASLD, providing protection while potentially participating in disease progression. The fine-tuning of autophagy in MASLD development remains a hot research topic.

Taurine can increase autophagic flux in hepatocytes exposed to cadmium, primarily by regulating the SNARE family. Taurine treatment promotes the translocation of Syntaxin 17 (STX17) to autophagosomes, increasing the colocalization of LC3-II with STX17 and Synaptosome-Associated Protein 29 (SNAP29). It also promotes the translocation of Vesicle-Associated Membrane Protein (VAMP8) to lysosomes, increasing the colocalization of VAMP8 with LAMP2 [104]. Reports indicate that in mature adipose tissue of mice, taurine lowers ERK1/2 phosphorylation levels without altering the mTORC1 pathway, facilitating TFEB dephosphorylation and nuclear translocation, binding to the promoter regions of autophagy-related genes, thereby accelerating the transcription of these genes [105].

While autophagy provides protection against cell damage and inflammatory responses to some extent, excessive autophagy may exacerbate MASLD progression. During the NASH stage, over activated autophagy can lead to extensive hepatocyte death, further aggravating liver inflammation and fibrosis [106]. In mouse livers and HepG2 cells, taurine reverses arsenic-induced insulin resistance by activating the PPARγ-mTORC2 signaling pathway and inhibiting autophagy [107]. In PC12 cells, taurine activates mTOR, significantly reducing the expression of LC3-II, thereby decreasing autophagy to protect against methamphetamine-induced PC12 cell damage [108]. Studies also show that taurine pretreatment regulates the PPARγ/NF-κB pathway in the offspring liver of gestational diabetes mellitus (GDM) mice, reducing the number of autophagosomes and autophagy-related markers LC3-II and p62, thereby decreasing autophagy in the offspring hepatocytes [109].

Taurine’s modulation of autophagy underscores its potential as a therapeutic agent in MASLD. By fine-tuning autophagic processes, taurine helps maintain cellular homeostasis, reducing hepatocyte damage and mitigating disease progression.

Taurine and pyroptosis

Programmed cell death of macrophages plays a crucial role in the progression of MASLD. Since inflammasomes, which are central to pyroptosis, are mainly expressed in immune cells, particularly macrophages, pyroptosis of these cells significantly impacts the progression of MASLD. The NLRP3 inflammasome, composed of NLRP3 protein, apoptosis-associated speck-like protein (ASC), and pro-caspase-1, can sense danger signals through nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and control the activation of caspase-1, promoting the maturation of pro-inflammatory cytokines pro-IL-1β and pro-IL-18. Additionally, caspase-1 activation can directly induce pyroptosis [110]. The connection between NLRP3 inflammasome and MASLD/NASH pathogenesis is well-established. In the liver of MASLD patients, the mRNA levels of NLRP3, IL-1β, IL-18, and pro-caspase-1 are significantly elevated compared to healthy controls. Furthermore, in the liver of NASH patients, increased mRNA levels of inflammasome components (NLRP3, ASC, caspase-1) and IL-1β and IL-18 proteins are observed, along with elevated caspase-1 activity and IL-1β levels in both liver and serum [111]. Pyroptosis can promote NASH progression by inducing ROS release, amplifying pyroptosis and inflammatory cascades. Macrophage-specific Nrf2 knockdown enhances ROS and IL-1β production through a YAP-NLRP3 dependent mechanism, aggravating NASH progression, indicating the pro-inflammatory role of macrophage pyroptosis. The gasdermin family may target the mitochondrial membrane, inducing mtROS release, thereby triggering NLRP3 inflammasome activation. KC can activate the NLRP3 inflammasome through mitochondrial DNA (mtDNA) release, promoting NASH progression [46]. XBP-1, associated with ER stress, is observed in macrophages and can inhibit BNIP3, preventing its activation of the STING pathway and ultimately the NLRP3 inflammasome, with deficiency improving MASLD [112].

Taurine alleviates NASH induced by chronic arsenic exposure by inhibiting the pyroptosis-inflammasome pathway rather than improving lipid accumulation, emphasizing the connection between NLRP3 inflammasome activation and pyroptosis [113]. Activation of the NLRP3 inflammasome influences MASLD progression and disease severity by regulating hepatocyte inflammation-related pyroptosis [114]. Studies indicate that taurine alleviates hepatic fibrosis by inhibiting the TXNIP/NLRP3 inflammasome pathway. This involves downregulating the activation of NLRP3, ASC, caspase-1, and their downstream target GSDMD (gasdermin D). Inhibition of the TXNIP/NLRP3 inflammasome pathway by taurine reduces the activation and N-terminal cleavage of GSDMD, decreasing the formation of GSDMD pores on hepatocytes [115].

ER dysfunction is a significant factor related to hepatic damage caused by excess fatty acids, with ER stress being a crucial mechanism. ER stress includes a major pathway called the unfolded protein response (UPR), controlling the accumulation of liver proteins and lipids in cells. UPR reduces secretory protein load, enhances ER protein folding (chaperones and foldases transcription), and increases clearance capacity through promoting autophagy and ER-associated degradation (ERAD) [116]. Although transient UPR can prevent steatosis, chronic ER stress in MASLD exacerbates hepatic steatosis, with each pathway adversely affecting liver lipid pathways [117]. Growing evidence links ER stress with NLRP3 and hepatocyte pyroptosis. Genetic obesity in mice induces endotoxemia, triggering hepatic IRE1α and PERK activity, leading to CHOP overexpression, which regulates caspase-1 and caspase-11 expression, promoting hepatocyte pyroptosis [118]. Taurine significantly protects against arsenic-induced β-cell dysfunction by reducing IRE1α phosphorylation, TNF-α production, NLRP3 inflammasome activation, and pyroptosis [119]. Ten-week taurine feeding significantly reduces PERK, ATF6, and GPR78 expression in halibut liver, preventing high-carbohydrate-induced ER stress via ATF6 and PERK pathways rather than the IRE1 pathway. Taurine downregulates CHOP gene expression, indicating inhibition of CHOP-dependent pro-apoptotic signaling [120]. Taurine significantly inhibits ER stress signals induced by tunicamycin in mice, such as IRE1a, ATF6, XBP1, Bip, CHOP, and lipid uptake transporter CD36 expression, thereby inhibiting hepatic lipid accumulation [121].

Taurine and apoptosis

Taurine exhibits significant hepatoprotective functions against cadmium (Cd)-induced inflammation and apoptosis. Taurine alleviates Cd-induced hepatocyte vacuolization, nuclear condensation, mitochondrial swelling, and cristae dissolution. It significantly reduces serum ALT and AST levels and decreases hepatic inflammatory cytokines TNF-α and IL-1β levels. Additionally, taurine treatment lowers the Bax/Bcl-2 ratio and caspase-3 protein expression levels, indicating its anti-apoptotic effects [122].

Taurine also prevents and treats liver damage induced by γ-ray irradiation in mice. It achieves this by downregulating apoptotic pathway markers such as NO, cytochrome-c, caspase-9, and caspase-3 in the liver [123]. In rice field eel injected with H2O2, the hepatic expression of bax, caspase-3, and beclin1 genes is significantly upregulated, while bcl2 and p62 gene expression is downregulated, leading to apoptosis. In contrast, dietary supplementation with 0.2% and 0.5% taurine significantly mitigates this damage, providing evidence for taurine’s protective effects on the liver [124]. In the offspring of gestational diabetes mice treated with taurine, the expression of apoptosis-related proteins caspase-3/caspase-3 and Bax is reduced, while Bcl2 expression is increased, effectively downregulating hepatocyte apoptosis [109].

Other types of RCD

In addition to apoptosis, taurine influences other types of RCD, such as ferroptosis, efferocytosis and immunogenic cell death (ICD), providing a comprehensive protective mechanism for hepatocytes.

Ferroptosis was initially described as a unique form of programmed cell death observed in cancer cells with oncogenic RAS mutations, distinct from apoptosis, necrosis, and autophagy at morphological, biochemical, and genetic levels [125]. Increasing research supports the crucial role of ferroptosis and lipid metabolism disorders in the progression of NASH. Inhibiting ferroptosis significantly reduces the severity of NASH [126]. Ptgs2 expression is upregulated during ferroptosis and is considered a marker of ferroptosis, while SLC7A11 and GPX4 are essential proteins regulating ferroptosis [127]. Intravenous injection of neutrophil membrane-encapsulated taurine nanoparticles reverses increased Ptgs2 expression and decreased SLC7A11 and GPX4 expression during hepatic ischemia-reperfusion injury, inhibiting the progression of hepatocyte ferroptosis and exerting protective effects on the liver.

TauCl is endogenously produced in activated neutrophils and released to the site of inflammation when these neutrophils undergo apoptosis. TauCl modifies cysteine residues in Keap1, potentially disrupting the interaction between Keap1, Nrf2, and the CUL3 ubiquitin ligase complex. The released transcription factor Nrf2 translocates to the nucleus, upregulating HO-1 expression and enhancing macrophage efferocytosis, which helps clear apoptotic neutrophils and prevents their accumulation and release of cellular contents that could trigger inflammation and tissue damage. CO produced by HO-1 may be involved in TauCl-induced efferocytosis during inflammation resolution, a mechanism that warrants further exploration [128].

In tumor immunotherapy, immune checkpoint inhibitors have been shown to enhance anti-tumor responses when combined with chemotherapeutic drugs or radiotherapy that induce ICD, a mechanism that includes ER stress-induced ICD, triggering protective anti-tumor immunity. In breast cancer cell studies, oleandrin primarily activates ATF3 and CHOP through the PERK-eIF2α-ATF4 and IRE1-XBP1 axes, inducing ER stress, which ultimately leads to CRT translocation to the cell surface, providing a “Eat-me” signal for DCs [129]. Previously, we established a connection between taurine and ER stress, with increasing evidence showing that dietary taurine helps reduce hepatic inflammation and ER stress induced by high dietary carbohydrate intake [120]. Taurine inhibits the increase of GRP78 mRNA and protein expression in turbot muscle cells under high glucose conditions, while reducing PERK mRNA expression, thereby inhibiting PERK-mediated Bax protein expression and cleaved caspase-3 protein expression, mitigating apoptosis [130] (Fig. 5).

Fig. 5.

Taurine and Regulated Cell Death (RCD) in MASLD

Early diagnosis and natural product therapy for MASLD

Early diagnosis of MASLD

Due to the significant impact MASLD can have on various systems, early diagnosis and treatment are crucial. Liver fibrosis is considered the strongest predictor of long-term clinical outcomes in MASLD patients. Accurately assessing the stages of NASH and fibrosis is challenging, often requiring liver biopsy for diagnosis confirmation. However, liver biopsy is an invasive procedure with associated risks, highlighting the importance of non-invasive MASLD detection methods, which are currently a major focus of research.

In a recent study, a new scoring system known as the SAFE score was developed for diagnosing MASLD in primary care. This score incorporates seven variables: gender, BMI, diabetes status, ALT, AST, platelets, and globulin. The SAFE score performs significantly better than NFS and FIB-4, and it is at least as good as, if not better than, three commonly used machine learning models [131]. Another review highlighted that biomarkers such as FIB-4, NFS, and APRI can effectively stratify patients’ liver-related morbidity and mortality risks, performing comparably to liver biopsy [132]. Additionally, research has indicated that among vitamin B12-related biomarkers, red blood cell folate is independently associated with MASLD, while MMA and HCY are independently associated with the risk of advanced fibrosis in MASLD, suggesting that HCY and MMA may be candidate biomarkers for predicting MASLD fibrosis [133]. Further, it was demonstrated that measuring liver stiffness using transient elastography (FibroScan) and FibroMeterV2G is more accurate for non-invasive liver fibrosis diagnosis compared to BRAD, NFS, FibroMeterMASLD, APRI, FIB-4, Fibrotest, and Hepascore, though limitations prevent definitive conclusions about the superiority of these methods [134]. Moreover, the evaluation of magnetic resonance elastography (MRE) and magnetic resonance imaging proton density fat fraction (MRI-PDFF) for non-invasive assessment of MASLD, finding that MRE’s prognostic accuracy for predicting fibrosis improvement was 0.62 (0.46–0.78), while MRI-PDFF’s AUC for predicting steatosis reduction was 0.70 (0.57–0.83) [135].

NASH represents the most severe form of MASLD, characterized by hepatocyte ballooning and inflammation. Developing non-invasive detection methods for NASH, akin to those for MASLD, remains a research priority. A blood-based diagnostic test named NIS4, includes four independent biomarkers: miR34a, HbA1c, α2-macroglobulin (A2M), and YKL-40. NIS4 outperforms FIB-4 and NFS in diagnosing NASH [4]. Additionally, NIS4 shows better performance than other non-invasive tests, including FIB-4, NFS, ELF™, BRAD, APRI, and VCTE [136]. Sanyal AJ et al. conducted a systematic evaluation of five NASH diagnostic methods (including NIS4, OWliver, PROC3, ELF, and FibroMeter VCTE) and found that NIS4 meets pre-specified standards for further qualification for diagnosing NASH, high NAS, and high-risk NASH. ELF test and FibroMeter VCTE meet standards for diagnosing clinically significant fibrosis (stage 2 and above), advanced fibrosis (stage 3 and above), and cirrhosis (stage 4) in MASLD patients [137]. In April 2023, Harrison SA et al. developed an optimized version of the NIS4 model called NIS2+™,, which refines HbA1c and α2-macroglobulin markers. This new model shows reduced influence from age, T2DM status, and gender [136] (Table 1).

Table 1.

Early diagnosis of MASLD

Diagnostic methods	Disease	Reference
The SAFE score	low-risk MASLD	[131]
Device-assisted Elastography	liver fibrosis	[131]
FIB-4	liver fibrosis	[138]
NFS	the prediction of advanced fibrosis	[139]
APRI	the prediction of advanced fibrosis	[140]
RBC folate	MASLD	[133]
HCY and MMA	advanced fibrosis risk in MASLD	[133]
LSM and FibroMeterV2G	liver fibrosis in MASLD	[134]
MRE and MRI-PDFF	fibrosis as assessed by liver biopsy	[135]
NIS4	non-alcoholic steatohepatitis and liver fibrosis	[4]
NIS2+™	non-alcoholic steatohepatitis and liver fibrosis	[136]
ELF™	moderate and severe fibrosis, moderate fibrosis and cirrhosis	[141, 142]
BARD	advanced non-alcoholic liver disease (MASLD)	[143]
VCTE	significant fibrosis (≥ F2) and with cirrhosis (= F4)	[144]
PROC3(ADAPT)	MASLD and advanced fibrosis (≥ F3)	[145]
NHDS	MASLD-HCC	[146]

Natural products and MASLD

Current treatment strategies for MASLD, given its associated risk factors such as unhealthy lifestyle, IR, type 2 diabetes mellitus (T2DM), increased hepatic lipogenesis, and gut microbiota dysbiosis, include both non-pharmacological and pharmacological approaches. Non-pharmacological strategies encompass dietary changes, exercise interventions, and bariatric surgery. Strict caloric restriction, induction of ketosis, reduction of free sugar intake, and carbohydrate restriction can enhance liver protection, making dietary interventions a promising strategy for treating MASLD [147]. Regular exercise has been shown to improve MASLD in both non-obese and obese patients [148]. The American Society for Metabolic and Bariatric Surgery Pediatric Committee (ASMBS) recommends metabolic and bariatric surgery (MBS) as an effective treatment for severe obesity in adolescents, though it is relatively rare in China [149].

Pharmacological strategies include medications for T2DM (GLP-1 receptor agonists, SGLT2 inhibitors, biguanides, thiazolidinediones), lipid-lowering drugs (statins, cholesterol absorption inhibitors), antihypertensive drugs, hepatoprotective agents (UDCA, FXR agonists), probiotics/prebiotics/synbiotics targeting the gut microbiota, PPAR agonists, thyroid hormone receptor β agonists (THR-β agonists), fibroblast growth factor analogs (FGF19/FGF21), and newly developed DNL inhibitors (ACC inhibitors, FAS inhibitors, SCD1 inhibitors, DGAT inhibitors, ketohexokinase inhibitors, MPC inhibitors), miRNAs, and nanoparticles as drug delivery systems. Given the critical role of IR in MASLD development, antidiabetic drugs are commonly used in clinical treatment of T2DM patients with MASLD. Dyslipidemia in MASLD patients often manifests as elevated triglycerides and LDL-C levels, and decreased HDL-C levels, with hepatic cholesterol deposition contributing to MASLD progression. Thus, lipid-lowering drugs can be used to treat MASLD [150]. Elevated blood pressure is associated with the progression of fatty liver disease and fibrosis in patients, making antihypertensive drugs useful in MASLD treatment [151]. UDCA and FXR agonists possess antioxidant and anti-inflammatory properties, preventing mitochondrial dysfunction in obesity-related diseases, and can improve glucose control and IR.

However, some of the aforementioned treatments have side effects, such as poor patient compliance and specific adverse reactions with most lipid-lowering drugs, and there are currently no targeted drugs approved for treating NASH. Consequently, natural products (NPs) have gained attention. Due to their high activity and low side effects, they have become an important source for developing new MASLD drugs. Major natural products include flavonoids, polyphenols, terpenoids, saponins, alkaloids, and quinones [152]. They can treat MASLD by regulating lipid metabolism, antioxidative stress, inflammatory response, and cell death (Table 2).

Table 2.

Natural product therapeutic strategies for MASLD

Pathway	Types of NPs	Cell or Animal model	Refference
Lipid Metabolism
Inhibiting mTOR-SREBP-1 to Suppress Lipid Synthesis	Scutellarin	PA-treated HepG2 cells: 0.1, 1, 10, 100, and 200 µM for 24 h; HFD-induced C57BL/6 mice: 50 or 150 mg/kg/d, 18d	[153]
	Curcumin	OPA-induced primary mouse hepatocytes: 10 µM for 24 h; HFD-induced mice: 50 or 150 mg/kg, 18w	[154]
Enhancing Sirt1-Foxo to Alleviate Endoplasmic Reticulum Stress and Promote Autophagy, Thereby Mitigating Lipid Metabolic Disorders	Resveratrol	HFD-induced rats: 200 mg/kg.bw,18 w;	[155]
	Resveratrol	PA-induced HepG2 cells: 20, 40, and 80 µM for 24 h; HFD-induced rats: RSV0.4%, 4w	[156]
	Berberine	FFA-induced HepG2 cells: 1, 5, and 25 µg/mL for 24 h	[157]
	Ginsenoside Rg2	OA/PA-induced Mouse Primary Hepatocytes(MPHs): 25µM Rg2 for 24–48 h; HFD-induced C57BL/6J mice: 2.5, 5, and 10 mg/kg/d, 4w	[158]
Activating the cAMP-PRKA pathway to inhibit SREBP1c and suppress lipid synthesis, while also activating PPARα to inhibit hepatic TG synthesis and increase fatty acid oxidation	Resveratrol	PA-induced HepG2 cells: 40 µM for 24 h; HFD-induced rats: 20 mg/kg, 8w;	[159]
	Resveratrol	PA-induced HepG2 cells: 20, 40, and 80 µM for 24 h; HFD-induced rats: RSV0.4%, 4w	[156]
	Demethyleneberberine	HepG2 cells: 0–50 µM for 24 h; MCD-induced ICR mice: 20 or 40 mg/kg/d, 4w	[160]
	Bouchardatine	DMEM-induced 3T3-L1 fibroblast and HepG-2 cells: 25 µM, 9d	[161]
Enhancing Sesn2 to inhibit LXRα and suppress SREBP-1c, thereby reducing lipid synthesis	Resveratrol	Primary hepatocytes from HFD mice: 30 µM for 24 h; HFD -fed mice: 0.4% w/w, 8w	[162]
Inhibiting the m6A demethylase AlkB homolog 5 (ALKHB5) to promote THDF1 and TRAF4, which in turn inhibit PPARγ and lipid synthesis	Curcumin	HFD-induced mice: 100 mg/kg/d, 12w	[163]
Promoting TGR5 to enhance the cAMP/PKA signaling pathway, increasing the expression of uncoupling protein 1 (UCP1) to boost thermogenesis	Curcumin	HFD-fed wild type, Ucp1 KO and TGR5 KO mice: 100 mg/kg/d in vivo, 24w	[164]
	Betulinic acid	HFD-induced mice: 30 mg/kg/d, 3w	[165]
Activating FXR to inhibit the PERK/EIF2α/ATF4/CHOP pathway to alleviate endoplasmic reticulum stress	Betulinic acid	DMEM-induced HepG2 cells: 6, 12, 25, and 50µM for 24 h; HFD-induced C57BL/6 mice: 100 mg/100 g, 6w	[166]
Increasing UCP1 expression through the SIRT1-LKB1-AMPK pathway	Bouchardatine	HFD-induced C57BL/6 mice: 50 mg/kg/d, 5w	[167]
Directly inhibiting or binding to the LXRα ligand to suppress angiopoietin-like protein 3 (ANGPTL3) and enhance LPL activity, thereby exerting lipid-lowering effects	Naringenin	HepG2 and Huh-7 cells: 5, 10, 20, 40, and 60µM for 24 h	[168]
Downregulating the expression of CD36 and PPARγ to reduce FFA uptake	Naringin	tissue-engineered fatty (TEF) livers: 10µM for 24 h	[169]
Combining with SIRT3 to improve fatty acid metabolism disorders in MASLD	Protocatechuic acid	PA-induced AML-12 cells: 10µM for 24 h; HFD-induced rats: 20 mg/kg/day, 8w	[170]
	Resveratrol	I-deficient human fibroblasts: 75 µM for 48 h	[171]
	Berberine	HFD-induced C57BL/6 mice: 300 mg/kg/d, 4w	[172]
Improving MASLD by inhibiting free fatty acid uptake through the HDAC1/PPARG axis	Ferulic Acid and p-Coumaric Acid	FFA-treated hepatocytes: 60 µg/mL for 24 h; HFD-induced mice: 30 mg/kg/day, 13 weeks	[173]
Increasing the expression of PPARα and CPT1 to promote fatty acid oxidation (BBR regulates epigenetic modifications by promoting MTTP)	Naringin	Tissue-engineered fatty (TEF) livers: 10µM for 24 h	[169]
	Berberine	DMEM-induced BRL cells: 20 µM BBR for 72 h; HFD-induced SD rats: 200 mg/kg/d, 8w	[174]
	Ginsenoside Rg1	HFD-induced SD rats: 30 or 60 mg/kg/d, 4w	[175]
	Ursolic acid (UA)	HFD-induced C57BL/6J mice: 50 or 200 mg/kg, 8w	[176]
Anti-inflammation
Activating the PPARγ/AMPK-Nrf2 pathway to inhibit oxidative stress and improve mitochondrial function	Scutellarin	OA-induced HepG2 cells: 50, 100, and 200 mmol/L for 24 h; HFD-induced C57BL/6 mice: 12.5, 25, and 50 mg/kg/d, 8w	[177]
	Apigenin	FFA-induced Hepa1-6 cell: 10 µM for 2 h; HFD-induced C57BL/6J mice: 30 mg/kg, 3w	[178]
	Cordycepin	PA + OA -induced L02 cells: 50 and 100 µM for 12 h; HFD-induced mice: 100 or 200 mg/kg/d, 8w	[179]
Activating the AMPK pathway to inhibit insulin resistance and oxidative stress	Scutellarin	HFD-induced C57BL/6 mice: 50 mg/kg/d, 16w	[180]
	Chrysin	Insulin-resistant HepG2 cells: 15 µM for 24 h; HFD/STZ-induced C57BL/6 J mice: 30 mg/kg, 5w	[181]
	Ferulic acid (FA)	DMEM-induced MPH/LX-2 cells: 12.5,25, and 50µM for 24 h; CCl4-induced C57BL/6 mice: 25, 50, and 100 mg/kg, 4w	[182]
Activating the PPARγ/FGF21-PGC-1α pathway to improve mitochondrial function	Scutellarin	OA-induced HepG2 cells: 50, 100, and 200 mmol/L for 24 h; HFD-induced C57BL/6 mice: 12.5, 25, and 50 mg/kg/d, 8w	[177]
	Chrysin	Fructose-induced IR rats: 100 mg/kg/d, 6d	[183]
Inhibiting NLRP3 to suppress the inflammatory response	Quercetin	HFD-induced ApoE−/− mice; 100 mg/kg, 16w; ox-LDL-induced RAW264.7 cell: 50 µg/mL for 24 h	[184]
	Berberine	LPS/PA-induced AML12 cells: 10 or 20µM for 24 h; MCD-induced C57BLKS/J mice: 100 mg/kg/d, 5w	[185]
	Cordycepin	PA + OA -induced L02 cells: 50 and 100 µM for 12 h; HFD-induced mice: 100 or 200 mg/kg/d, 8w	[179]
Programmed cell death
Inhibiting the IRE1α-XBP1-Foxo pathway to alleviate endoplasmic reticulum stress and promote autophagy	Scutellarin	PA-treated HepG2 cells: 10, 30, and 50 µM for 24 h; HFD-induced C57BL/6 mice: 50 or 150 mg/kg, 18d	[186]
	Quercetin	FFA-induced HepG2: 24 h; HFD-induced Sprague-Dawley rats: 100 mg/kg, 8w	[187]
Regulating the epigenetic TFEB-P300-BRD4 axis to promote autophagy	Curcumin	ox-LDL-induced THP-1 cells: 20 µM for 24 h; Apoe KO mice: 20 mg/kg, 16w	[188]
Promoting Bmi-1 to inhibit the P53/P21 pathway and suppress apoptosis	Scutellarin	OA-induced HepG2 cells: 50, 100, and 200 mmol/L for 24 h; HFD-induced C57BL/6 mice: 12.5, 25, and 50 mg/kg/d, 8w	[177]
	Chrysin	Fructose-induced IR rats: 100 mg/kg/d, 6d	[183]
Upregulating AMPK to inhibit TGF-β, thereby suppressing adipose tissue fibrosis	Berberine	HFD-induced C57BL/6 mice: 75 mg/kg/d or 150 mg/kg/d, 4w	[189]

As the pathogenesis of MASLD continues to be refined, beneficial natural products have been identified and applied to mitigate the progression of MASLD. Although taurine is not traditionally classified as a natural product, it can still be obtained through dietary sources. Historically, taurine was deemed non-essential because it does not participate in protein synthesis in the human body. However, with advancements in science and technology, numerous epidemiological studies have demonstrated that taurine helps prevent cardiovascular diseases such as hypertension, stroke, ischemic heart disease, and atherosclerosis [190].

While taurine is endogenously synthesized from methionine and cysteine, the majority of taurine is acquired through diet, found in seafood, meats, poultry, and eggs. Seafood, particularly fish and shellfish, are considered the primary dietary sources of taurine, indicating its high availability [191]. As previously discussed, taurine has shown positive effects on liver function. Although there are no phase I or II clinical trials specifically investigating taurine for MASLD, a double-blind clinical trial has shown that taurine supplementation in liver transplant patients can alleviate certain mental disorders [192]. This provides insight and confidence for conducting taurine-related clinical trials for MASLD.

Conclusion

This review has comprehensively outlined the pathogenesis of Non-Alcoholic Fatty Liver Disease (MASLD), current diagnostic and therapeutic approaches, and the role of natural products in its treatment. MASLD’s pathogenesis is predominantly linked to lipid metabolism disorders, oxidative stress, and endoplasmic reticulum (ER) stress. Additionally, the gut-liver axis, mediating epigenetic modifications and immune metabolism, plays a significant role in MASLD. This paper proposes that taurine, a non-traditional natural product, could be used in treating MASLD. By aligning taurine’s bile-acid conjugation and antioxidant actions with the gut–liver axis, adjunct taurine therapy is mechanistically positioned to lower endotoxin load, blunt hepatic inflammatory tone, and improve lipid handling in MASLD.

Despite taurine’s promising role as a naturally occurring amino acid in mitigating MASLD, clinical trials focusing on its efficacy are limited. Preliminary studies indicate taurine’s potential in reducing oxidative stress and inflammation and improving metabolic profiles in MASLD models. However, extensive clinical research is needed to validate these findings and ascertain the precise mechanisms through which taurine exerts its protective effects. The limited availability of clinical data underscores the necessity for further trials to evaluate taurine’s therapeutic potential comprehensively.

Current therapeutic strategies for MASLD are diverse, ranging from lifestyle modifications and surgical interventions to pharmacological treatments targeting various metabolic pathways. While lifestyle changes, such as diet and exercise, are fundamental, pharmaceutical approaches often involve anti-diabetic, lipid-lowering, and anti-hypertensive medications. Emerging treatments, including FXR agonists, PPAR agonists, and novel agents targeting DNL pathways, show promise but also highlight the complexity of MASLD treatment. Natural products, including taurine, offer a complementary approach by potentially addressing multiple facets of the disease through their multi-targeted effects.

Looking forward, integrating taurine into the therapeutic arsenal for MASLD requires rigorous clinical trials to establish its efficacy and safety. High-quality clinical trials should be conducted, with priority given to well-designed randomized controlled trials, to evaluate the efficacy of taurine in patients at different stages of MASLD. Determining the optimal therapeutic dose, administration frequency and course of taurine in different populations, seeking specific biomarkers that can predict the therapeutic response of taurine or monitor its efficacy, and understanding the interaction between taurine and other therapeutic drugs are crucial for formulating a comprehensive treatment plan. At present, there are no clear clinical trials indicating the reasonable dosage of taurine for MAFLD, but we can still refer to the dosage of taurine in other diseases: For instance, a randomized controlled trial on Alzheimer’s disease pointed out that volunteers in the active intervention group who took whey protein powder containing 4 g/100 g taurine every day showed positive therapeutic effects after the corresponding treatment cycle. This feedback also provides us with a great inspiration for future medication guidance. Additionally, research should focus on elucidating the molecular pathways through which taurine modulates MASLD progression, particularly its effects on the gut-liver axis and immune response. This will enhance our understanding of taurine’s role in liver health and its potential integration into mainstream therapeutic strategies.

In conclusion, taurine presents a promising adjunct in the treatment of MASLD. Its ability to modulate key pathological processes offers hope for developing effective and safe treatment options. However, the current lack of extensive clinical evidence necessitates further research to fully realize taurine’s potential in MASLD management. Future studies should aim to clarify its mechanisms of action, optimal dosing regimens, and long-term safety profiles, thereby paving the way for its integration into comprehensive MASLD treatment protocols.

Abbreviations

5FU

5-fluorouracil

A2M

α2-macroglobulin

ACC

Acetyl-CoA carboxylase

AS

Alternative splicing

ASC

Apoptosis-associated speck-like protein

ASMBS

American Society for Metabolic and Bariatric Surgery Pediatric Committee

Atg

Autophagy-related genes

Bas

Bile acids

BSH

Bile salt hydrolase

cAMP

Cyclic adenosine monophosphate

CCL2

CC-chemokine ligand 2

CCR2

CC-chemokine receptor 2

CDO

Cysteine dioxygenase

ChREBP

Carbohydrate-responsive element-binding protein

circRNAs

Circular RNAs

CPT1a

Carnitine palmitoyltransferase1a

CSA

Cysteine sulfinic acid

CSAD

Cysteine sulfinic acid decarboxylase

CSD

Cysteine sulfinic acid decarboxylase

CYP7A1

Cytochrome P450 family member 7A1

DAMPs

Damage-associated molecular patterns

DCs

Dendritic cells

DGAT2

Diacylglycerol Acyltransferase 2

DIO

Diet-induced obesity

DIZE

Diacetyldiazenium diolate

DNL

De novo lipogenesis

DNMTs

DNA methyltransferases

DPP-4

Dipeptidyl peptidase-4

ER

Endoplasmic reticulum

ERAD

ER-associated degradation

ETC

Electron transport chain

FAO

Fatty acid oxidation

FAs

Fatty acids

FAS

Fatty acid synthase

FFAs

Free fatty acids

FGF21

Fibroblast growth factor 21

FMO1

Flavin-containing monooxygenase 1

FXR

Farnesoid-X Receptor

GDM

Gestational diabetes mellitus

GPx

Glutathione peroxidase

GSDMD

Gasdermin D

GSSG

Oxidized glutathione

GST

Glutathione-S-transferase

H3K4

H3 lysine 4

HCC

Hepatocellular carcinoma

HDACs

Histone deacetylases

HDMs

Histone demethylases

HMTs

Histone methyltransferases

HNF4α

Hepatocyte nuclear factor 4α

HO-1

Heme oxygenase-1

HOCl

Hypochlorous acid

HRG

Histidine-rich glycoproteins

HSCs

Hepatic stellate cells

ICD

Immunogenic cell death

IDE

Insulin-degrading enzyme

IECs

Intestinal epithelial cells

IFN-γ

Interferon-γ

ILCs

Innate lymphoid cells

iNKT

Invariant NKT

IR

Insulin resistance

KCs

Kupffer cells

LEPR

Leptin receptors

lncRNAs

Long ncRNAs

LPO

Lipid peroxidation

LPS

Lipopolysaccharide

LSM

Liver Stiffness Measurement

LXRα

Liver X receptor α

MAIT

Mucosal-associated invariant T

MASLD

Metabolic dysfunction associated with steatotic liver disease

MBS

Metabolic and bariatric surgery

MDA

Malondialdehyde

MELAS

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

MoMFs

Monocyte-derived macrophages

MRE

Magnetic resonance elastography

MRI-PDFF

Magnetic resonance imaging proton density fat fraction

mtDNA

Mitochondrial DNA

MTO1

Mitochondrial translation optimization 1

NAFLD

Non-alcoholic fatty liver disease

NASH

Non-alcoholic steatohepatitis

ncRNA

Non-coding RNA

ncRNAs

Non-coding RNAs

NK

Natural killer

NOD

Nucleotide-binding oligomerization domain

NPC1L1

Niemann-Pick C1-Like 1

NPs

Natural products

NR2F6

Nuclear receptor subfamily 2, group F, member 6

Nrf1

Nuclear factor E2-related factor 1

Nrf2

Nuclear factor E2-related factor 2

PGC1-α

PPAR-γ coactivator 1-α

PINK1

PTEN-induced putative kinase 1

piRNAs

Piwi-interacting RNAs

PNPLA3

Patatin-like phospholipase domain-containing 3 gene

PPARα

Proliferator-activated receptor α

RCD

Regulated cell death

ROS

Reactive oxygen species

SCD1

Stearoyl-CoA desaturase 1

SCFAs

Short-chain fatty acids

SDH

Succinate dehydrogenase

SIRTs

Sirtuins

SNAP29

Synaptosome-Associated Protein 29

sncRNAs

Small ncRNAs

snRNAs

Small nuclear RNAs

SOD

Superoxide dismutase

SRA

Scavenger receptor A

SREBP-1

Sterol regulatory element-binding protein-1

SREBP-1c

Sterol Regulatory Element Binding Protein-1c

SREBPs

Sterol regulatory element-binding proteins

SREs

Sresponse elements

STX17

Syntaxin 17

T2DM

Type 2 diabetes mellitus

TAUT

Taurine transporter

TCA

Taurocholic acid

TCDCA

Taurochenodeoxycholic acid

TDCA

Taurodeoxycholic acid

Tfam

Mitochondrial transcription factor A

TG

Triglyceride

TGF-β

Transforming growth factor-β

TGR5

Takeda G-protein-coupled receptor 5

THR-β

Thyroid hormone receptor β

TLCA

Taurolithocholic acid

TLRs

Toll-like receptors

TNF

Tumor necrosis factor

TNFα

Tumor necrosis factor-α

TPN

Total parenteral nutrition

TUDCA

Tauroursodeoxycholic acid

UPR

Unfolded protein response

VAMP8

Vesicle-Associated Membrane Protein

VLDL

Very low-density lipoproteins

Authors’ contributions

Lu F Y and Meng L. prepared the manuscript draft; Ma Y J, Zhang B. and Gao J. performed review and editing.

Funding

No funding was received for this study.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.