Targeting Ferroptosis in Sepsis: Therapeutic Potential and Mechanisms of Natural Products and Traditional Chinese Medicine

Abstract

Sepsis is a life-threatening organ dysfunction driven by a dysregulated host response to infection, yet targeted pharmacological therapies remain severely limited. Emerging evidence highlights ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, as a pivotal mechanism underlying sepsis pathogenesis and subsequent multiple organ dysfunction syndrome (MODS). While the pathological relevance of ferroptosis is well-established, comprehensive reviews exploring the potential of Traditional Chinese Medicine (TCM) and natural bioactive compounds to therapeutically modulate this pathway in sepsis remain scarce. This review systematically evaluates diverse TCM-derived phytochemicals, including flavonoids, terpenoids, alkaloids, and polyphenols, elucidating their molecular mechanisms in attenuating sepsis-induced ferroptosis. Specifically, we detail how these natural products mitigate multi-organ injury by restoring iron homeostasis, quenching lipid peroxidation cascades, and upregulating core antioxidant axes, notably the Nrf2/SLC7A11/GPX4 signaling pathway. By synthesizing current preclinical evidence encompassing isolated bioactive compounds and classical TCM formulae, this review aims to clarify the pharmacological rationale of TCM in sepsis management, offering novel insights for the discovery of innovative therapeutic targets and the development of precision medicine strategies.

Introduction

Sepsis is a life-threatening organ dysfunction syndrome caused by dysregulated host response to infection whose pathophysiological process is highly complex, involving immune-inflammatory imbalance, immunosuppression, coagulation dysfunction, oxidative stress, metabolic reprogramming, and multi-organ dysfunction. Hosts often activate multiple defense and damage-related responses simultaneously during sepsis progression; failure to restore immune homeostasis and internal environment balance may lead to further progression to multiple organ failure or even death.¹ As a major global public health concern, sepsis affects approximately 50 million patients and causes 11 million deaths annually, imposing substantial burdens on healthcare systems and socioeconomic development worldwide.² However, a substantial proportion of sepsis survivors develop post-sepsis syndrome (PSS), a condition characterized primarily by persistent cognitive impairment, physical functional decline, psychological disturbances, and sustained organ dysfunction.³ Current sepsis treatment primarily focuses on infection control, hemodynamic support, and host response modulation, with an evolving trend toward personalized therapeutic approaches.⁴ Various therapeutic strategies targeting sepsis-induced immune dysregulation are currently under active investigation. These encompass immunostimulatory agents designed to reverse immune exhaustion (such as interleukin-7[IL-7], granulocyte-macrophage colony-stimulating factor [GM-CSF], and anti-PD-1/PD-L1 antibodies), alongside anti-inflammatory or cytoprotective approaches such as NLRP3 inflammasome inhibitors, cytokine and pattern recognition receptor antagonists, and modulators of regulated cell death. Despite these extensive efforts, broadly applicable and standardized targeted therapies have yet to be established in clinical practice.⁵ Therefore, further elucidation of the key molecular mechanisms underlying sepsis pathogenesis, particularly the identification of novel cell death pathways and their intervention targets, holds significant importance for advancing precision treatment of sepsis.

Ferroptosis, first described in 2012, represents a distinct form of regulated cell death that differs from apoptosis and is closely associated with iron metabolic dysregulation. Excess free iron can react with lipid peroxides, leading to abnormal accumulation of intracellular lipid reactive oxygen species (ROS) and ultimately triggering cell death.⁶ Accumulating evidence has confirmed the close relationship between ferroptosis and sepsis development.⁷ Intracellular iron overload may trigger lipid peroxidation through Fenton reactions and subsequently induce ferroptosis.^8,9 Once initiated, ferroptotic cells can release excessive intracellular iron to promote bacterial overgrowth and exacerbate infection,^10,11 or release damage-associated molecular patterns (DAMPs) such as high mobility group box 1 (HMGB1) and lipid peroxidation products including 4-hydroxynonenal (4-HNE) to activate inflammatory signaling pathways, thereby amplifying inflammation and causing tissue and organ damage that worsens sepsis progression.^12,13 These findings provide novel perspectives for in-depth understanding of sepsis pathogenesis and offer a scientific basis for sepsis intervention strategies targeting ferroptosis modulation.

In recent years, the therapeutic potential of traditional Chinese medicine (TCM) and natural active substances in sepsis treatment has attracted increasing attention.¹⁴ Existing studies indicate that natural products and TCM compound formulae can ameliorate sepsis-related pathological damage at multiple levels, with mechanisms potentially involving regulation of immune-inflammatory responses, protection of vascular endothelial function, alleviation of oxidative stress, and maintenance of mitochondrial homeostasis.¹⁵ Concurrently, research on natural products intervening in sepsis through ferroptosis modulation has shown a growing trend. Evidence demonstrates that various natural active constituents, including flavonoids, terpenoids, and alkaloids, can inhibit sepsis-related ferroptosis to varying degrees, thereby alleviating organ damage and improving disease outcomes.^16–18 Targeting ferroptosis with natural products may exert dual therapeutic benefits: it alleviates acute organ injury in the early phase of sepsis and may subsequently reduce the risk of PSS, which further underscores the clinical translational potential of this therapeutic strategy.^19,20

While several critical challenges must be addressed before these findings can be effectively translated into clinical practice, including a lack of high-quality clinical evidence, difficulties in standardizing TCM products, and insufficient interdisciplinary collaboration, emerging nanodelivery strategies offer promising solutions. Approaches such as liposome-encapsulated formulations and targeted nanoparticles can overcome these pharmacokinetic hurdles by enhancing drug solubility. For instance, M12-liposome nanoparticles have demonstrated targeted delivery to skeletal muscle and sustained release of therapeutic agents in sepsis-induced muscle atrophy, whereas mRNA nanotherapeutics highlight the potential for precise immune modulation in sepsis via advanced lipid nanoparticle systems.^14,21,22 Ultimately, investigating natural products and traditional medicines that target ferroptosis in sepsis is essential for achieving precision medicine.

Although previous reviews have discussed the role of ferroptosis in sepsis development, systematic summaries specifically addressing TCM and natural active substances that modulate ferroptosis for sepsis intervention remain limited. Based on this context, this review focuses on ferroptosis, systematically summarizes its mechanisms in mediating sepsis pathogenesis including key regulatory factors and signaling pathways, and further compiles research evidence and potential molecular foundations of TCM and natural products improving sepsis through ferroptosis modulation, aiming to provide novel insights for mechanistic research and clinical intervention strategy development in sepsis.

Methods

Search Strategy

The relevant studies published until March 2026 were extracted from four databases: PubMed, Web of Science, Google Scholar, and ScienceDirect. The primary keywords used included “ferroptosis in sepsis”, “targeting ferroptosis in sepsis”, “ferroptosis inhibition”, “improving/alleviating sepsis”, “natural products”, “traditional Chinese medicine”, and their combinations.

Inclusion/Exclusion Criteria

Studies were included if they focused on: (1) ferroptosis mechanisms in sepsis; (2) anti-ferroptotic mechanisms in sepsis; (3) traditional Chinese medicine, herbal extracts, or phytochemicals; and (4) in vitro or in vivo experiments. Exclusion criteria were: (1) insufficient data; (2) non-English language; (3) unavailable full text; (4) duplicate publications.

The Mechanism of Ferroptosis in Sepsis

Building upon the established pathological framework of ferroptosis in sepsis, the following sections will systematically dissect the molecular machinery governing this process. We will first delineate the core regulatory networks, including iron metabolism dysregulation, lipid peroxidation cascades, and the antioxidant defense systems, with particular emphasis on the cystine/glutamate antiporter system Xc- (System Xc-)-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis, the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) signaling cascade and more pathways. Subsequently, we will elaborate on how these pathways interconnect to amplify organ damage during septic progression, and how natural products precisely intervene at multiple nodes within this intricate network. The underlying mechanisms are illustrated in Figure 1 (created with BioGDP).²³

Figure 1.

The mechanism of ferroptosis in sepsis.

Iron Metabolism Disorder

Sepsis alters iron metabolism at both systemic and cellular levels. Iron is transported from the extracellular environment to intracellular compartments as ferric iron (Fe³⁺) via transferrin receptor 1 on the cell membrane.²⁴ Within endosomes, Fe³⁺ is reduced to ferrous iron (Fe²⁺) by iron reductases such as six-transmembrane epithelial antigen of prostate 3 (STEAP3),²⁵ and subsequently released into the cytoplasm through divalent metal transporter 1 to participate in the synthesis of iron-dependent enzymes.²⁶ Excess Fe²⁺ is typically stored in the labile iron pool or sequestered in ferritin composed of ferritin heavy chain 1 (FTH1) and ferritin light chain (FTL).²⁷ Ferroportin 1 (FPN) is the only known cellular iron exporter,²⁸ and its deficiency represents a critical factor contributing to iron overload and ferroptosis initiation.²⁹ The toxicity of iron originates from Fenton reactions between Fe²⁺ and Fe³⁺, which generate reactive oxygen species (ROS) that damage lipids, proteins, and DNA, thereby triggering ferroptosis.³⁰ Autophagy, particularly ferritinophagy, amplifies ferroptosis by degrading ferritin to increase free iron availability while enhancing transferrin receptor 1 expression.³¹

Lipid Peroxidation

Ferroptosis is defined as iron-dependent peroxidation of phospholipids containing polyunsaturated fatty acids (PUFAs), resulting in plasma membrane disruption.³² Driven by the conversion of Fe²⁺ to Fe³⁺, Fenton/Haber-Weiss reactions transform H₂O₂ into hydroxyl radicals (HO•), which subsequently react with polyunsaturated lipids (LH), including PUFAs, to generate lipid radicals (L•) and initiate lipid peroxidation.³³ Following initiation, the propagation phase involves reactions between L• and additional LH to produce lipid hydroperoxides (LOOH) and regenerate L•. LOOH reacts with Fe²⁺ and Fe³⁺ to form alkoxyl radicals (LO•) and peroxyl radicals (LOO•), respectively. Iron-containing lipoxygenases, such as arachidonate-15-lipoxygenase (ALOX15), also catalyze the reaction between O₂ and LH to generate LOOH,³⁴ as iron constitutes an essential component of the catalytic subunit.³⁵ In sepsis, ROS generated by mitochondria and other oxidase systems peroxidize these lipids, while excess Fe²⁺ catalyzes non-enzymatic Fenton reactions and iron-containing enzymes (such as lipoxygenases) mediate enzymatic peroxidation. The critical determinant of lipid peroxidation in ferroptosis is cellular membrane composition, particularly the presence of PUFAs, which are highly susceptible to autoxidation—a free radical chain reaction converting lipids into LOOH.³⁶ Accumulation of LOOH compromises membrane integrity, ultimately leading to ferroptotic cell death.³⁷ Extensive oxidation of PUFA-phospholipids alters membrane structure and permeability, causing necrosis-like rupture and release of damage-associated molecular patterns (DAMPs) that exacerbate inflammation. Collectively, iron-dependent lipoxygenases initiate ferroptosis, whereas iron-driven Fenton reactions propagate this process.³⁸

Regulatory Factors and Pathways of Ferroptosis in Sepsis

GPX4-GSH

The system Xc⁻-GSH-GPX4 axis serves as the primary pathway regulating ferroptosis.³⁹ Multiple mechanisms can lead to GSH depletion, including inhibition of system Xc⁻ transporter, reduced cystine uptake, and impaired GSH synthesis.⁴⁰ GPX4 inactivation similarly involves multiple mechanisms: beyond substrate deficiency resulting from GSH depletion, GPX4 protein itself can suffer oxidative damage and nitrification modifications; increased free iron ions generate substantial •OH through Fenton reactions, directly attacking GPX4 selenocysteine residues and causing irreversible inactivation; and proteolytic enzymes such as calpains become activated during cellular stress, cleaving and degrading GPX4 protein. The protective role of the GPX4-GSH axis has been well established in sepsis-associated acute kidney injury (SA-AKI). During sepsis, renal tissue exhibits characteristic ferroptosis features: significantly decreased GSH levels, reduced GPX4 expression, elevated malondialdehyde (MDA) and 4-HNE, and altered mitochondrial morphology.⁴¹

keap1-Nrf2

The Keap1-Nrf2 signaling axis is closely associated with ferroptosis, with Nrf2 serving as a critical transcriptional regulator of GPX4 expression.⁴² The GPX4 gene promoter region contains functional antioxidant response element (ARE) sequences; binding of Nrf2-sMaf heterodimers activates transcription. In sepsis models, Nrf2 activators such as naringenin significantly upregulate GPX4 protein levels, whereas Nrf2 knockdown abolishes this effect, confirming the functional connection of the Nrf2-GPX4 axis.⁴³ This regulatory mechanism positions Nrf2 as an upstream regulatory node of the GPX4-GSH axis, forming the Nrf2-GPX4-GSH cascade protective network. Under oxidative stress conditions, cysteine residues of Keap1 undergo modifications, leading to conformational changes that subsequently trigger Nrf2 dissociation and promote its translocation to the nucleus.⁴⁴

Other Signaling Pathways

Ferroptosis-suppressor-protein 1 (FSP1) was initially termed AIFM2 due to its structural similarity with the pro-apoptotic mitochondrial protein AIF (AIFM1). Current evidence suggests that FSP1 complemented the inactivation of GPX4 in osteosarcoma cells and MCF7 ferroptosis resistant cell lines.⁴⁵ Thus, FSP1 may be a ferroptosis suppressor independent of GPX4, and the expression level of FSP1 determines the sensitivity of cells to ferroptosis.⁴⁶ Emerging evidence has established a critical link between the FSP1-CoQ10-NAD(P)H axis and sepsis-associated organ dysfunction. In SA-AKI, the Nrf2/SLC7A11/FSP1/CoQ10 pathway is markedly suppressed, manifesting as reduced FSP1 and CoQ10 levels, elevated NAD+/NADH ratios, and accumulation of lipid peroxidation products including MDA and 4-HNE.⁴⁷ Notably, further investigation demonstrated that STING activation suppresses FSP1 expression in septic endothelial cells, driving ferroptosis. STING inhibition with H-151 restored FSP1 levels, reduced Fe²⁺ overload whereas FSP1 knockdown abolished these protective effects, confirming FSP1 as the critical downstream effector linking innate immune signaling to endothelial barrier collapse in sepsis.⁴⁸

Studies have demonstrated that aberrant inflammatory responses are critical to iron metabolic dysregulation and redox system imbalance.⁴⁹ In sepsis, nuclear factor-kappa B (NF-κB) and ferroptosis form a dangerous positive feedback loop: NF-κB activation drives inflammatory responses, generating substantial ROS and reactive nitrogen species (RNS) that induce lipid peroxidation and trigger ferroptosis;⁵⁰ ferroptotic cells release DAMPs (such as HMGB1 and oxidized phospholipids), further activating Toll-like receptors (TLRs) and NOD-like receptors (NLRs) to reinforce NF-κB signaling;⁵¹ meanwhile, iron ions and fatty acids released from ferroptosis provide nutrients for pathogen growth, exacerbating infection and inflammation.⁴¹ This self-amplifying loop not only accelerates organ dysfunction but also creates a microenvironment conducive to bacterial persistence, highlighting the intertwined nature of ferroptosis and inflammation in sepsis pathogenesis.

Intervention of Ferroptosis in Sepsis by Natural Products and TCM

Natural products and TCM have a long history of application in the prevention and treatment of diseases, largely owing to their pleiotropic effects and diverse multi-target pharmacological profiles. In recent years, the research value of natural products and TCM in the field of sepsis intervention has become increasingly prominent. Existing evidence indicates that they exert anti-inflammatory, antioxidant, and organ-protective effects through multi-target pathways. As research into the pathogenesis of sepsis deepens, ferroptosis has gained attention as a key cell death modality mediating the pathological process of sepsis, prompting investigations into the potential therapeutic value of natural products in regulating sepsis-associated ferroptosis. This section systematically reviews the pharmacodynamic characteristics and molecular mechanisms of natural products and TCM with regulatory activity against sepsis-associated ferroptosis, aiming to provide a theoretical basis and research directions for expanding the application of natural products and TCM in sepsis treatment and discovering novel therapeutic targets. The pharmacological details, experimental models, and ferroptosis-related mechanisms of these natural products and TCM formulations are systematically summarized in Tables 1 and 2.

Table 1.

Summary of Natural Products Targeting Ferroptosis in Sepsis

Name	Source	Dose	Model	Clinical Manifestation	Mechanisms Associated with Ferroptosis	Ref.
Quercetin	Fruits and vegetables	20 and 40 mg/kg in vivo 80 μM in vitro	SD rats (CLP-induced cardiomyopathy model) H9C2 cardiomyocytes (LPS-induced) Human serum samples	Reduce serum levels of CK-MB and cTnI Decrease inflammatory cell infiltration in myocardial tissues Ameliorate cardiac function	Activate the SIRT1/p53/SLC7A11 signaling pathway Upregulate GPX4, ferritin, TOM20 expression and increase GSH content Downregulate PTGS2 expression, Fe2⁺, MDA and NADPH levels Attenuate lipid peroxidation and mitochondrial damage	[52]
		15, 30 and 45 μM in vitro	Human AC16 cardiomyocytes (LPS-induced) Human serum samples	Alleviate cardiomyocyte injury Reduce the levels of IL-1β and TNF-α Inhibit cell apoptosis	Downregulate ALOX5 expression Activate the PI3K/AKT signaling pathway Decrease the levels of Fe2⁺ and ROS Increase the levels of GSH and GPX4	[53]
Hyperoside	Fruits, vegetables, flowers, and medicinal plants	10, 30 and 50 mg/kg in vivo Pretreatment intervention in vitro	C57BL/6 mice (CLP-induced ALI model) MLE-12 cells (LPS-induced)	Improve survival rate in septic mice Reduce lung inflammation, pulmonary edema, and neutrophil infiltration Decrease serum TNF-α and IL-6 levels	Bind Keap1 (Arg380/415) and disrupt Keap1-Nrf2 interaction Inhibit Nrf2 ubiquitination and promote its nuclear translocation Upregulate GPX4, SLC7A11 transcription and increase intracellular GSH content Decrease Fe2⁺ level and lipid peroxidation	[54]
Baicalein	Scutellaria baicalensis Georgi	1, 10 and 100 mg/kg in vivo 5, 10 and 20 μM in vitro	C57BL/6 mice (LPS-induced myocardial injury) H9C2 cardiomyocytes (LPS-induced)	Improve cardiac function, increase EF and FS, decrease LVESD and LVEDD Attenuate myocardial fiber disarray and inflammatory cell infiltration Decrease serum levels of CK-MB, LDH, CRP, IL-6, IL-1β, and TNF-α Alleviate cardiomyocyte injury	Upregulate miR-299b-5p expression miR-299b-5p targets and inhibits HIF1-α expression Increase GPX4 expression	[55]
Wogonin	Scutellaria baicalensis Georgi	20, 40, 60 mg/kg in vivo 10 μM in vitro	C57BL/6 mice (CLP-induced cardiomyopathy model) HL-1 cardiomyocytes (LPS-induced)	Improve survival rate in septic mice Improve cardiac function, increase LVEF and LVFS Decrease serum levels of cTnI, CK-MB, and LDH Attenuate myocardial inflammation and oxidative stress	Directly bind to and inhibit ALOX15 activity Downregulate ALOX15 downstream metabolites 15-HpETE and 15-HETE Decrease MDA and 4-HNE levels, attenuate lipid peroxidation and mitochondrial damage Restore GPX4 expression and GSH/GSSG ratio Downregulate PTGS2 expression	[56]
Tangeretin	Tangerine and citrus fruits	50 mg/kg in vivo 25 μM in vitro	ICR mice (LPS-induced ALI model) RAW264.7 macrophages (LPS-induced)	Alleviate lung histopathological damage Decrease lung W/D ratio and bronchoalveolar lavage fluid (BALF) protein content Reduce MPO activity and F4/80⁺ macrophage infiltration Decrease lung tissue levels of IL-6, IL-1β, and TNF-α, and promote macrophage M2 polarization	Activate Nrf2 signaling pathway, upregulate Nrf2 and HO-1, downregulate Keap1, and promote Nrf2 nuclear translocation Upregulate GPX4, downregulate PTGS2 Decrease MDA, 4-HNE and Fe2⁺ levels, increase GSH content Reduce ROS accumulation and lipid peroxidation	[43]
Fortunellin	Kumquat (Fortunella japonica Swingle)	30 mg/kg in vivo 20, 40, 80 μM in vitro	C57BL/6 mice (CLP-induced AKI model) HK-2 cells (LPS-induced)	Reduce BUN and Cr levels, improve renal function Attenuate renal histopathological damage Improve cell viability and reduce apoptosis Decrease levels of IL-1β, IL-6, and TNF-α	Inhibit activation of the TLR4/NF-κB pathway, decrease p-IRAK4, p-p65, p-IκBα levels Decrease Fe2⁺ and MDA levels Increase SOD activity and GSH content	[57]
Ginsenoside Rb1	Panax ginseng C. A. Mey	20 mg/kg in vivo 40 μM in vitro	C57BL/6 mice (CLP-induced model, lung and intestine tissues) THP-1 cells (LPS-induced)	Attenuate pathological damage in lung and intestine tissues Decrease serum levels of IL-1β, IL-6, and TNF-α Improve cell viability	Directly bind to HO-1 and inhibit its expression Downregulate PTGS2 and upregulate GPX4 expression Decrease Fe2⁺ and MDA levels, increase GSH content	[58]
Andrographolide	Andrographis paniculata (Burm. f). Nees	10 and 40 mg/kg in vivo 1.25, 2.5, 5 μM in vitro	BALB/c mice (LPS-induced ALI model) RAW264.7 cells (LPS-induced)	Alleviate lung histopathological damage, reduce lung W/D ratio in ALI mice Downregulate IL-6, TNF-α, iNOS and COX-2 Enhance cell viability	Directly bind to TLR4 and suppress its expression Modulate Keap1/Nrf2 pathway, downregulate Keap1, promote Nrf2 nuclear translocation, upregulate HO-1 and NQO1 Upregulate GPX4 and SLC7A11, restore GSH levels Decrease Fe2⁺, MDA, ROS	[59]
Dihydroartemisinin	Artemisia annua L.	5 and 10 mg/kg in vivo 1 and 5 μM in vitro	C57BL/6 mice (CLP-induced SAE model) BV2 microglial cells (LPS-induced)	Improve survival rate and alleviate cognitive dysfunction Reduce neuronal death and microglial activation Decrease IL-1β, IL-6, TNF-α Reduce cell activation and migration	Directly bind to HIF1A and inhibit HIF1A/HMOX1 pathway Upregulate SLC7A11 and GPX4 expression Decrease Fe2⁺, MDA, LPO and ROS levels Restore mitochondrial function	[16]
5β-Hydroxycostic acid	Laggera alata (D. Don) Sch.-Bip. ex Oliv.	7.5 and 15 mg/kg in vivo 5, 10, 20 μM in vitro	C57BL/6 mice (CLP-induced AKI model) RAW264.7 cells (LPS-induced)	Alleviate renal histopathological damage Decrease serum levels of IL-6, IL-1β, Cr, BUN, Cys-C and KIM-1 Inhibit NO production and mRNA expression of pro-inflammatory factors in RAW264.7 cells	Inhibit phosphorylation of NF-κB and MAPK pathways Downregulate FTH1, upregulate SLC7A11 and GPX4 expression Decrease Fe2⁺ and MDA levels, increase GSH content	[17]
Tetramethylpyrazine (TMP)	Conioselinum anthriscoides “Chuanxiong”	25, 50, 100 mg/kg in vivo 40 μg/mL in vitro	C57BL/6 mice (CLP-induced liver injury model) AML12 mouse hepatocytes (LPS-induced)	Alleviate liver histopathological damage and hepatic fibrosis Decrease IL-6, TNF-α, ALT and AST Increase IL-10 Enhance cell viability and proliferation, reduce apoptosis	Activate GPX4/Nrf2/FSP1 signaling pathway Upregulate mRNA and protein expression of GPX4, Nrf2 and FSP1 Downregulate mRNA and protein expression of Atf3 and TFR1	[60]
Coptisine	Coptis chinensis Franch.	20 and 40 mg/kg in vivo 5 and 10 μg/mL in vitro	C57BL/6 mice (CLP-induced AKI model) HK2 cells (LPS-induced)	Decrease serum BUN and Cr levels Alleviate renal histopathological damage Reduce TNF-α, IL-6, IL-1β in kidney tissues Enhance cell viability	Activate Nrf2 signaling pathway, upregulate Nrf2 and GPX4 expression Decrease ROS, MDA and Fe2⁺ levels Increase GSH content	[61]
Isoferulic acid (IFA)	Actaea cimicifuga L.	12.5 and 25 mg/kg in vivo 20, 30, 40 μM in vitro	C57BL/6 mice (CLP-induced liver injury model) AML12 mouse hepatocytes (erastin-induced)	Alleviate liver histopathological damage, decrease serum ALT and AST levels Reduce mRNA levels of TNF-α, IL-6, IL-1β Enhance cell viability	Directly bind to SIRT1 and activate SIRT1 signaling pathway Upregulate Nrf2, GPX4 and xCT expression Decrease Fe2⁺, MDA, FTH and FTL levels, increase GSH and SOD levels Restore mitochondrial membrane potential (MMP)	[62]
Cinnamaldehyde	Cinnamomum cassia Presl	40 mg/kg in vivo 5, 10, 20 μM in vitro	C57BL/6 mice (LPS-induced AKI model) HK-2 cells (LPS-induced)	Alleviate tubular injury, decrease serum Cr and BUN Decrease serum IL-6, IL-1β, TNF-α, MCP-1 Enhance cell viability	Identify GSK3β as a core target Inhibit GSK3β expression, activate Nrf2, upregulate GPX4, downregulate ACSL4 Decrease renal MDA, Fe2⁺, and LPO levels	[63]
Resveratrol	grapes, berries, and red wine	10, 30 and 50 mg/kg in vivo 25 μM in vitro	SD rats (CLP-induced cardiomyopathy model) H9c2 rat cardiomyocytes (LPS-induced)	Improve cardiac function, increase LVEF, LVFS; decrease LVEDV, LVESV, LVIDs in CLP rats Decrease serum CK-MB and LDH levels, alleviate myocardial histopathological damage	Activate SIRT1/Nrf2 signaling pathway Upregulate GPX4 and FTH1, downregulate ACSL4 and TFR Decrease MDA, 4-HNE, Fe2⁺ and ROS levels, increase GSH content Restore mitochondrial morphology and membrane potential	[64]
Urolithin A	Pomegranates, strawberries, nuts	50 mg/kg in vivo 10 μM in vitro	C57BL/6 mice (LPS-induced model) BEAS-2B human bronchial epithelial cells (LPS-induced)	Alleviate lung histopathological damage, reduce lung W/D ratio, BALF protein content and neutrophil count Decrease TNF-α, IL-1β, IL-6 Improve cell viability	Activate Keap1-Nrf2/HO-1 signaling pathway Upregulate GPX4 and SLC7A11 Decrease Fe2⁺, 4-HNE and MDA levels Increase SOD, CAT and GSH-Px activities Reduce ROS levels	[65]

Table 2.

Summary of Traditional Chinese Medicine Formulations Targeting Ferroptosis in Sepsis

Name	Source	Dose	Model	Clinical Manifestation	Mechanisms Associated with Ferroptosis	Ref.
XueBiJing injection (XBJ Injection)	Carthamus tinctorius, Paeonia lactiflora, Salvia miltiorrhiza, Conioselinum anthriscoides “Chuanxiong”, and Angelica sinensis	Dose not specified in vivo 20× dilutions in vitro	SD rats (CLP-induced ALI) BEAS-2B human lung epithelial cells (LPS-induced)	Improve survival rate Decrease lung W/D ratio, alleviate lung histopathological damage Reduce serum and cellular IL-6, TNF-α Decrease ROS and Fe2⁺ levels	Decrease Fe2⁺, MDA, GSSG, ROS levels, increase GSH and GSH/GSSG ratio Reveal enrichment of glycerophospholipid metabolism, phospholipid metabolism pathways Upregulate GPX4, xCT, FTH1; downregulate ACSL4	[66]
		9 mL/kg in vivo 10×, 20×, 40× dilutions in vitro	WT, CCR2−/−, Nrf2−/− C57BL/6 mice (CLP-induced and LPS-induced ALI model) THP-1, U937 human monocytic cells, primary mouse monocytes	Alleviate lung histopathological damage, decrease lung W/D ratio, Reduce IL-6, IL-1β, TNF-α Reduce pro-inflammatory monocyte infiltration Inhibit M1 macrophage polarization	Activate Nrf2/HO-1 pathway Increase lipid peroxidation, Fe2⁺, TFR1 Decrease GPX4, SLC7A11, FTH1	[67]
TaoHe ChengQi decoction (THCQD)	Rhei Radix et Rhizoma, Persicae Semen, Cinnamomum cassia, Glycyrrhizae Radix et Rhizoma, and Natrii Sulfas	2, 4 g/kg in vivo 50, 100, 200, 500 μg/mL in vitro	WT and Nrf2−/− C57BL/6 mice (CLP-induced cardiac dysfunction model) Neonatal rat cardiomyocytes (NRCMs) (RSL3-induced)	Improve survival rate, increase LVEF and LVFS, decrease LVDd and LVDs Alleviate myocardial histopathological damage Decrease serum cTnT, CK-MB, LDH, TNF-α, IL-6, and myocardial IL-1β	Activate Nrf2 signaling pathway, increase its nuclear translocation, upregulate Nrf2, HO-1, NQO1 Upregulate GPX4, downregulate TFR1 Decrease total iron and Fe2⁺ levels, increase GSH, decrease MDA Improve mitochondrial morphology and membrane potential	[68]
Dahuang Gancao decoction (DHGC)	Rheum palmatum L. and Glycyrrhiza uralensis	1, 2, 4 g/kg in vivo 10%, 20%, 40% medicated serum in vitro	WT and SIRT3−/− C57BL/6 mice (LPS-induced AKI model) HK-2 human renal tubular epithelial cells (erastin-induced)	Decrease serum BUN and SCr levels, alleviate renal histopathological damage Reduce serum IL-6, IL-1β, TNF-α Improve mitochondrial morphology	Activate SIRT3/NRF2 pathway: upregulate SIRT3, NRF2, GPX4; downregulate ACSL4 and Ac-NRF2 Promote NRF2 deacetylation and nuclear translocation Decrease Fe2⁺ and MDA levels, increase SOD and GSH levels	[69]
Wenqingyin (WQY)	Coptidis Rhizoma, Phellodendron Cortex, Scutellaria Radix, Gardeniae Fructus, Rehmanniae Radix Preparata, Paeoniae Alba Radix, Angelicae Sinensis Radix, and Chuanxiong Rhizoma	5.4, 10.8 g/kg in vivo 50, 100, 200 μg/mL in vitro	WT and Nrf2−/− C57BL/6 mice (LPS-induced liver injury model) LO2 human hepatocytes (erastin-induced)	Alleviate liver histopathological damage Decrease ALT and AST levels Reduce serum and liver IL-6, IL-1β, TNF-α Increase cell viability	Activate Nrf2 signaling pathway Upregulate Nrf2, HO-1, GPX4, SLC7A11, FSP1, downregulate PTGS2 Promote Nrf2 nuclear translocation Decrease Fe2⁺, MDA, ROS levels Increase SOD and GSH levels Restore mitochondrial membrane potential	[70]
QiShenYiQi pills (QSYQ)	Astragalus membranaceus (Fisch). Bunge, Salvia miltiorrhiza Bunge, Panax notoginseng (Burkill) F.H. Chen, and Dalbergia odorifera T.C. Chen	150, 300 mg/kg in vivo 10% medicated serum in vitro	C57BL/6 mice (CLP-induced ALI model) Hy926 human endothelial cells (LPS-stimulated THP-1 macrophage conditioned medium)	Alleviate lung histopathological damage, reduce lung injury score Decrease lung W/D ratio, BALF protein content, and Evans blue extravasation Decrease levels of TNF-α, IL-6, IL-1β Reduce endothelial cell death and restore ZO-1, occludin	Decrease RAGE and COX2 expression; increase SLC7A11 and GPX4 expression Decrease GSSG, MDA, ROS levels; increase GSH and GSH/GSSG ratio	[71]
YiQiFuMai injection (YQFM)	Panax ginseng C.A. Mey., Ophiopogon japonicus (Thunb). Ker Gawl., and Schisandra chinensis (Turcz). Baill.	0.23, 0.45, 0.9 mg/kg in vivo 0.1, 0.5, 1 mg/mL in vitro	SD rats (CLP-induced cardiomyopathy model) H9c2 rat cardiomyocytes (LPS-induced)	Improve survival rate Decrease serum cTnI, CK-MB, LDH levels Alleviate myocardial histopathological damage Increase cell viability	Upregulate xCT/GPX4 axis, increase SLC7A11, SLC3A2, GPX4 expression Decrease Fe2⁺, ROS, MDA, 4-HNE levels Increase GSH content and GSH/GSSG ratio	[72]

Flavonoids

Flavonoids are the most prevalent phenolic metabolites found in plants, fruits, and vegetables,⁷³ sharing a common diphenylpropane (C6-C3-C6) skeleton consisting of two aromatic rings (A and B) linked by a three-carbon bridge.⁷⁴ Most flavonoids contain phenolic hydroxyl groups, which endow them with favorable aqueous solubility, antioxidant, and free radical scavenging capacities, enabling them to inhibit lipid peroxidation induced by ferroptosis.^75–77 In addition, flavonoids possess excellent iron chelating ability, as moieties such as the 6,7-dihydroxyl structure, 3-hydroxyl-4-keto group, 2,3-double bond, and catechol B-ring in their molecules can bind to iron ions.⁷⁸ Relying on these antioxidant and iron-chelating activities, flavonoids have emerged as potential natural anti-ferroptotic agents.

Quercetin

Quercetin is a natural flavonoid widely found in vegetables and fruits, possessing various pharmacological activities including antioxidant, anti-inflammatory, and antibacterial effects.^79,80 Study demonstrated that in both a cecal ligation and puncture (CLP)-induced septic rat model and LPS-stimulated AC16 and H9c2 cardiomyocytes, quercetin effectively restored cell viability and mitigated myocardial inflammatory infiltration, iron deposition, and cardiac dysfunction. Furthermore, quercetin was shown to inhibit ferroptosis, as evidenced by decreased levels of Fe²⁺, ROS, MDA, and PTGS2, alongside increased GSH content and GPX4 expression. These effects were preliminarily validated in clinical samples from septic cardiomyopathy patients. Mechanistically, quercetin was found to activate the SIRT1/p53/SLC7A11 signaling axis, which subsequently upregulates the expression of GPX4 and solute carrier family 7 member 11 (SLC7A11), thereby ultimately suppressing ferroptosis. Concurrently, quercetin activates the PI3K/AKT pathway to downregulate arachidonate 5-lipoxygenase (ALOX5) expression; together, these dual mechanisms synergistically inhibit cardiomyocyte ferroptosis, inflammation, and apoptosis. Notably, the protective effects of quercetin were largely abrogated by SIRT1 knockdown or ALOX5 overexpression, strictly validating its reliance on these targets. Ultimately, quercetin alleviates sepsis-induced myocardial injury by orchestrating a multi-pathway blockade of ferroptosis, specifically driven by the SIRT1/p53/SLC7A11 and PI3K/AKT/ALOX5 signaling axes.^52,53

Hyperoside

Hyperoside (quercetin 3-O-β-D-galactopyranoside) is a naturally occurring flavonoid glycoside abundant in various dietary and medicinal plants.^81–83 Recent research has demonstrated that hyperoside significantly improved survival rates, attenuated pulmonary inflammatory infiltration and edema, and favorably regulated ferroptotic markers in a CLP-induced murine model of acute lung injury (ALI). Notably, utilizing single-cell RNA sequencing (scRNA-seq), they identified alveolar type II epithelial cells (AEC2s) as the primary cellular targets of ferroptosis. Corroborating these in vivo and transcriptomic findings, hyperoside mitigated cellular injury, curtailed lactate dehydrogenase (LDH) release, and suppressed lipid peroxidation in LPS-stimulated MLE-12 alveolar epithelial cells in vitro. Mechanistic investigations revealed that hyperoside directly binds to Keap1 at the Arg380 and Arg415 residues. This competitive binding disrupts the Keap1-Nrf2 interaction, thereby preventing Nrf2 ubiquitination and degradation, and facilitating its nuclear translocation. Upon entering the nucleus, Nrf2 binds to the promoters of GPX4 and SLC7A11, driving the transcription of these core anti-ferroptotic genes. Crucially, the protective efficacy of hyperoside was significantly abrogated by Nrf2 gene silencing or pharmacological inhibition with ML385. Collectively, these data illustrate that hyperoside ameliorates sepsis-associated ALI (SA-ALI) by directly targeting the Keap1/Nrf2 axis to suppress alveolar epithelial ferroptosis.⁵⁴

Baicalein

Baicalein is a flavonoid extracted from the roots of Scutellaria baicalensis Georgi, and is one of the main active components of Scutellaria baicalensis.⁸⁴ It exerts a variety of pharmacological activities including anti-inflammatory and antioxidant effects.^85,86 Baicalein exerts a protective role in sepsis-induced cardiomyopathy through non-coding RNA-mediated post-transcriptional regulation. In the LPS-induced mouse model of sepsis and H9C2 cardiomyocyte injury model, baicalein dose-dependently improved cardiac function, as evidenced by increased ejection fraction (EF) and fractional shortening (FS), decreased left ventricular end-systolic diameter (LVESD) and left ventricular end-diastolic diameter (LVEDD), reduced iron deposition and lipid peroxidation in myocardial tissues, inhibited the release of inflammatory cytokines, and normalized ferroptosis-related indicators. Mechanistically, baicalein upregulated the expression of miR-299b-5p. Dual-luciferase reporter assay confirmed that miR-299b-5p directly bound to the 3’ untranslated region (3’UTR) of hypoxia-inducible factor 1-alpha (HIF1-α) and inhibited its expression, thereby blocking the progression of cardiomyocyte ferroptosis. This effect was significantly reversed by HIF1-α overexpression. The ferroptosis inhibitor ferrostatin-1 (Fer-1) enhanced the protective effect of baicalein, while the ferroptosis inducer erastin attenuated it. These findings suggest that baicalein improves sepsis-induced cardiomyopathy by inhibiting ferroptosis via the miR-299b-5p/HIF1-α pathway.⁵⁵

Wogonin

Wogonin is an active flavonoid derived from the roots of Scutellaria baicalensis Georgi, exhibiting a broad spectrum of pharmacological properties, including anti-inflammatory, antioxidant, and anti-apoptotic effects.^85,86 Current studies indicated that pretreatment with wogonin improved survival rates, ameliorated CLP-induced cardiac dysfunction, reduced myocardial injury marker elevation, and reversed cardiomyocyte contraction abnormalities in a CLP-induced septic cardiomyopathy mouse model and LPS-stimulated HL-1 cardiomyocyte injury model. Wogonin also significantly reduced inflammatory infiltration, oxidative stress, and mitochondrial dysfunction in myocardial tissues, while inhibiting cardiomyocyte ferroptosis. Mechanistic studies revealed that wogonin directly bound to and inhibited the activity of the lipoxygenase ALOX15, reduced the levels of its downstream products 15-hydroperoxyeicosatetraenoic acid (15-HpETE) and 15-hydroxyeicosatetraenoic acid (15-HETE), thereby blocking the peroxidation of polyunsaturated fatty acid phospholipids (PL-PUFAs) and inhibiting ferroptosis initiation. The ALOX15-specific inhibitor ML351 mimicked the protective effect of wogonin, while ALOX15 overexpression or 15-HpETE supplementation significantly attenuated its anti-ferroptotic effect. These results demonstrate that wogonin improves sepsis-induced cardiomyopathy by targeting and inhibiting the ALOX15/15-HpETE pathway, suppressing cardiomyocyte ferroptosis.⁵⁶

Tangeretin

Tangeretin is a naturally occurring polymethoxylated flavonoid abundant in the peels of citrus fruits,⁸⁷ exhibiting various pharmacological benefits including antioxidant, anti-inflammatory, neuroprotective, and anti-apoptotic activities.^88,89 In the LPS-induced mouse model of ALI, tangeretin alleviated the pathological damage of lung tissues, reduced the lung wet/dry ratio and total protein content in bronchoalveolar lavage fluid (BALF), while promoting the polarization of macrophages towards the anti-inflammatory M2 phenotype. In vitro experiments confirmed that tangeretin inhibited LPS-induced release of inflammatory cytokines and ferroptosis in RAW264.7 macrophages. Mechanistically, tangeretin activated the Nrf2 signaling pathway, promoted Nrf2 nuclear translocation, upregulated the expression of heme oxygenase-1 (HO-1) and GPX4, and downregulated PTGS2 expression, thereby mitigating iron accumulation and lipid peroxidation. Nrf2 knockdown via siRNA or treatment with the Nrf2 inhibitor ML385 reversed the inhibitory effects of tangeretin on ferroptosis and inflammation. Collectively, tangeretin ameliorates SA‑ALI by activating the Nrf2 signaling pathway and inhibiting macrophage ferroptosis.⁴³

Fortunellin

Fortunellin is a representative citrus flavonoid glycoside primarily isolated from the fruit of kumquat (Fortunella japonica Swingle).^90,91 As a naturally active flavonoid, fortunellin has been confirmed to possess various pharmacological activities including anti-inflammatory, antioxidant, and immunomodulatory effects.^92,93 Studies found that fortunellin dose-dependently improved cell viability, alleviated renal tubular pathological damage and renal dysfunction, and simultaneously inhibited the inflammatory response and ferroptosis progression in the CLP-induced mouse model of AKI and LPS-induced human renal tubular epithelial HK-2 cell model. Mechanistically, fortunellin inhibited the toll-like receptor 4 (TLR4)/NF-κB signaling pathway, downregulating the phosphorylation levels of interleukin-1 receptor-associated kinase 4 (IRAK4), p65, and inhibitor of NF-κB alpha (IκBα). This effect not only blocked the excessive inflammatory response, but also inhibited inflammation-mediated disorders of iron metabolism and lipid peroxidation, ultimately breaking the vicious cycle between inflammation and ferroptosis.⁵⁷

Terpenoids

Terpenoids, also known as isoprenoids, are a large and structurally diverse class of natural products derived from isoprene units.⁹⁴ As a major category of plant secondary metabolites, they are widely distributed in the plant kingdom. According to the number of constituent isoprene units, terpenoids are mainly classified into monoterpenes, sesquiterpenes, diterpenes, triterpenes and other subclasses.⁹⁵ The diversity of their carbon skeletons and oxygen-containing substituents collectively determines their broad spectrum of biological activities. Most terpenoids exhibit high lipophilicity due to their hydrophobic skeletons, which enables them to readily penetrate cell membranes and confers advantages for transdermal or pulmonary absorption.⁹⁶ Accumulating studies have demonstrated that terpenoids exert a wide range of pharmacological activities owing to their structural diversity, including anti-inflammatory, antioxidant, antibacterial and antitumor effects.⁹⁷ These intrinsic properties endow terpenoids with promising application potential in the regulation of ferroptosis, and also provide a new scientific basis for exploring their therapeutic value in sepsis and other diseases closely associated with oxidative stress and inflammation.

Ginsenoside Rb1

Ginsenoside Rb1, one of the main bioactive components of the precious traditional Chinese medicine Panax ginseng C. A. Mey., is a dammarane-type tetracyclic triterpenoid saponin.⁹⁸ Modern pharmacological studies have shown that ginsenoside Rb1 possesses a wide range of biological activities, including anti-inflammatory, antioxidant, anti-apoptotic and immunomodulatory functions.⁹⁹ Ginsenoside Rb1 ameliorated sepsis-induced organ injury by inhibiting ferroptosis. In the CLP-induced mouse model of sepsis and the LPS-induced THP-1 cell model, ginsenoside Rb1 significantly alleviated histopathological damage to lung and intestinal tissues, reduced systemic inflammatory factor levels, and simultaneously reversed abnormalities in ferroptosis-related indicators. Bioinformatics analysis identified HO-1 as the core regulatory gene of ferroptosis in sepsis. Further surface plasmon resonance (SPR) and microscale thermophoresis (MST) assays confirmed that ginsenoside Rb1 can directly bind to HO-1 protein and inhibit its overexpression, thereby blocking iron ion release and the chain reaction of lipid peroxidation. The HO-1 inhibitor zinc protoporphyrin (Znpp) could mimic the anti-ferroptotic effect of ginsenoside Rb1. This study revealed a novel mechanism by which ginsenoside Rb1 targets HO-1 to inhibit ferroptosis and ameliorate sepsis-related organ dysfunction.⁵⁸

Andrographolide

Andrographolide is a core active terpenoid compound from the Acanthaceae plant Andrographis paniculata (Burm. f). Nees, exhibiting diverse pharmacological activities including anti-inflammatory, antiviral, antibacterial, antioxidant, and tissue-protective effects, demonstrating potential applications in inflammatory diseases such as ALI and enteritis.^100–103 In the LPS-induced ALI mouse model and RAW264.7 macrophage model, andrographolide dose-dependently alleviated lung histopathological damage, reduced the lung wet/dry ratio and inflammatory cell infiltration, suppressed inflammatory cytokine release, and corrected abnormalities in ferroptosis-related biochemical indicators. Mechanistic studies demonstrated that andrographolide can directly target and bind to TLR4, thereby downregulating Keap1, promoting Nrf2 nuclear translocation, and activating the expression of downstream HO-1, NAD(P) H quinone dehydrogenase 1 (NQO1), GPX4 and SLC7A11. The TLR4 inhibitor TAK-242 could mimic part of the effects of andrographolide, while the Nrf2 inhibitor ML385 reversed its protective effects. In summary, andrographolide improves SA-ALI by targeting the TLR4/Keap1/Nrf2 pathway to inhibit inflammation and ferroptosis.⁵⁹

Dihydroartemisinin

Dihydroartemisinin (DHA), an important semi-synthetic derivative of artemisinin, is the core bioactive sesquiterpene lactone component of Artemisia annua L., a plant of the Artemisia genus in the Asteraceae family. It is also a first-line clinical antimalarial drug, and its diverse pharmacological activities including anti-inflammatory, immunomodulatory and anti-fibrotic effects have been gradually explored in recent years.^104,105 Compared with artemisinin, DHA has higher bioavailability and lower toxicity.¹⁰⁶ A study demonstrated that DHA exerts a protective effect against sepsis-associated encephalopathy (SAE). In the CLP-induced mouse model of SAE and the LPS-stimulated BV2 microglia model, DHA significantly improved the survival rate of mice, ameliorated cognitive dysfunction, inhibited microglial activation and neuronal ferroptosis, and alleviated mitochondrial dysfunction. Mechanistically, DHA can directly target and bind to HIF1A protein, inhibit the activation of the HIF1A/heme oxygenase 1 (HMOX1) signaling pathway to reduce iron ion release, and simultaneously upregulate the SLC7A11/GPX4 pathway to enhance antioxidant defense capacity. The HIF1A agonist dimethyloxalylglycine (DMOG) could partially reverse its protective effects. Collectively, DHA improves SAE by targeting the HIF1A/HMOX1 pathway, inhibiting microglial iron accumulation and mitochondrial dysfunction.¹⁶

5β-Hydroxycostic Acid

5β-Hydroxycostic acid is a sesquiterpenoid compound isolated from Laggera alata (D. Don) Sch. -Bip. ex Oliv., a traditional Chinese medicinal herb.^17,107 In the CLP-induced mouse model of AKI, 5β-hydroxycostic acid significantly improved renal function and alleviated histopathological damage to renal tubules. 5β-Hydroxycostic acid inhibited nitric oxide (NO) production in LPS-stimulated RAW264.7 macrophages (IC₅₀ = 6.034 μM) and downregulated the mRNA expression of inflammatory factors. Mechanistic studies revealed that 5β-hydroxycostic acid modulated ferroptosis-related indicators, as evidenced by decreased levels of MDA and Fe²⁺ levels, increasing GSH content, upregulating GPX4 and SLC7A11 expression, and downregulating FTH1 expression. Meanwhile, it synergistically regulated inflammation and ferroptosis via inhibiting the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways. Therefore, 5β-hydroxycostic acid improves SA-AKI by targeting the NF-κB and MAPK pathways to inhibit inflammation and ferroptosis.¹⁷

Alkaloids

Alkaloids are a diverse class of nitrogen-containing secondary metabolites synthesized by plants.¹⁰⁸ The core structural feature of alkaloids is the presence of a nitrogen-containing heterocycle, with the nitrogen atom typically derived from amino acid biosynthetic pathways. Based on their biosynthetic origins and characteristics of the nitrogen heterocycle, they can be classified into indole, isoquinoline, pyridine, quinoline, and diterpene alkaloids, among others. Isoquinoline and indole alkaloids are the most extensively studied categories, exhibiting anti-ferroptotic potential in various disease models. Some alkaloids with phenolic hydroxyl structures also possess direct free radical scavenging ability.^109,110 Owing to their unique nitrogen-containing heterocyclic structures and potent biological activities, alkaloids have become an important natural source for the development of novel ferroptosis inhibitors.

Tetramethylpyrazine (TMP, Ligustrazine)

Tetramethylpyrazine (TMP), also known as ligustrazine, is an alkaloid extracted from the perennial herb Conioselinum anthriscoides “Chuanxiong” of Umbelliferae.¹¹¹ TMP exhibits activities including anti-inflammatory, antioxidant, anti-apoptotic effects, and protection against organ ischemia-reperfusion injury, and is widely used in cardiovascular and cerebrovascular diseases as well as diabetic nephropathy.^112,113 In the CLP-induced septic liver injury mouse model, TMP alleviated histopathological damage and fibrosis of liver tissues, reduced serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and inflammatory factor levels, and decreased hepcidin content in liver tissues and myeloperoxidase (MPO) content in spleen tissues. In in vitro experiments, TMP inhibited the release of inflammatory factors from LPS-stimulated AML12 hepatocytes, enhanced cell viability, promoted cell proliferation and suppressed apoptosis. Mechanistically, TMP inhibited the expression of transferrin receptor 1 (TFR1) and activating transcription factor 3 (Atf3), and upregulated the expression of GPX4, Nrf2 and ferroptosis suppressor protein 1 (FSP1). Fer-1 enhanced the protective effect of TMP, while the ferroptosis inducer erastin reversed its effect. In conclusion, TMP improves sepsis-induced liver injury by inhibiting ferroptosis via the GPX4/Nrf2/FSP1 signaling pathway.⁶⁰

Coptisine

Coptisine is a protoberberine-type isoquinoline alkaloid extracted from the traditional Chinese herb Coptis chinensis Franch.¹¹⁴ As a traditional medicine, Huang Lian possesses properties of clearing heat, drying dampness, and purging fire, with its main active components including berberine, coptisine, and epiberberine.^115,116 Modern pharmacological studies have shown that coptisine possesses a variety of pharmacological activities, including anti-inflammatory, antioxidant, antibacterial, antitumor and neuroprotective effects.¹¹⁷ In the CLP-induced AKI mouse model, coptisine treatment significantly alleviated histopathological damage of renal tissues, reduced serum blood urea nitrogen (BUN) and creatinine (Cr) levels, and downregulated the expression of inflammatory factors in renal tissues. In in vitro experiments, coptisine inhibited the release of inflammatory factors from LPS-stimulated HK2 human renal tubular epithelial cells, reversed abnormalities in ferroptosis-related indicators, and enhanced cell viability. Mechanistic studies revealed that coptisine upregulated the expression of Nrf2 and GPX4, and its protective effect could be reversed by Nrf2 knockdown or iron supplementation. Collectively, coptisine ameliorates SA-AKI by activating the Nrf2 signaling pathway to inhibit ferroptosis.⁶¹

Phenylpropanoids

Phenylpropanoids are a class of natural secondary metabolites with a C6-C3 carbon skeleton as the basic structural unit, which are widely distributed in the plant kingdom.¹¹⁸ Based on differences in the linkage between the benzene ring and the propane chain, as well as substituent variations, they can be divided into subclasses such as simple phenylpropanoids, coumarins, and lignans. These compounds exhibit potent antioxidant capacity, which may be mainly achieved through scavenging free radicals, inhibiting lipid peroxidation, chelating metal ions and binding to antioxidant enzymes.¹¹⁹ The antioxidant potential of phenylpropanoids depends on their structural configuration, especially the number and arrangement of phenolic hydroxyl groups on the aromatic ring. With their abundant sources and pleiotropic antioxidant mechanisms, phenylpropanoids have become important drug candidates for the prevention and treatment of ferroptosis-related diseases.

Isoferulic Acid (IFA)

Isoferulic acid (IFA) is a phenolic acid compound extracted from the rhizomes of Actaea cimicifuga L., and it is a natural derivative of cinnamic acid.¹²⁰ Modern pharmacological studies have shown that IFA possesses various activities including anti-inflammatory, antioxidant and free radical scavenging effects, making it potentially useful for treating diabetes, inflammatory diseases, neurodegenerative disorders, and cardiovascular diseases.^121,122 A study found that IFA alleviated histopathological damage of liver tissues, reduced serum transaminase levels, inhibited the release of inflammatory factors, and simultaneously corrected abnormalities in ferroptosis-related biochemical indicators in the CLP-induced mouse model of liver injury and the erastin-induced AML12 hepatocyte model. Mechanistic studies demonstrated that IFA can directly bind to SIRT1 via SPR assay, thereby upregulating the expression of Nrf2 and its downstream target proteins GPX4 and xCT, and inhibiting ferroptosis. The SIRT1 inhibitor EX-527 or SIRT1 knockdown via SIRT1-siRNA could reverse the protective effect of IFA. In summary, isoferulic acid improves sepsis-induced liver injury by inhibiting ferroptosis via activation of the SIRT1-Nrf2 signaling pathway.⁶²

Cinnamaldehyde

Cinnamaldehyde is an aromatic aldehyde compound extracted from the bark, branches, and leaves of Cinnamomum cassia Presl, a major active component of cinnamon with various pharmacological activities including antioxidant, anti-inflammatory, antibacterial, anti-diabetic, anti-obesity, and anticancer effects.^123–126 In the LPS-induced mouse model of sepsis-associated acute kidney injury, cinnamaldehyde treatment significantly reduced serum Cr and BUN levels, alleviated histopathological damage of renal tissues, and reversed abnormalities in ferroptosis-related indicators. High-throughput screening of 100 natural products revealed that cinnamaldehyde exerted the strongest protective effect against LPS-induced injury in HK-2 renal tubular epithelial cells, as evidenced by enhanced cell viability and reduced inflammatory levels. Mechanistically, network pharmacology and molecular docking identified glycogen synthase kinase 3β (GSK3β) as its core target. Cinnamaldehyde blocked the ferroptosis process by inhibiting GSK3β activity, upregulating the expression of Nrf2 and GPX4, and downregulating the expression of acyl-CoA synthetase long-chain family member 4 (ACSL4). Overexpression of GSK3β completely reversed its renal protective and anti-ferroptotic effects. Therefore, cinnamaldehyde improves sepsis-induced AKI by inhibiting ferroptosis via the GSK3β/Nrf2/GPX4 pathway.⁶³

Polyphenols

Polyphenols are important secondary metabolites widely distributed in higher plants, with a core molecular structure of an aromatic ring skeleton linked to two or more phenolic hydroxyl groups. They serve as key precursors for various natural medicines, and the phenolic hydroxyl groups confer good polarity and reactivity, allowing them to regulate molecular metabolic processes in organisms.¹²⁷ While flavonoids represent the most abundant and systematically studied subclass of polyphenols, this section focuses on non-flavonoid polyphenolic compounds, which similarly possess the core antioxidant properties of polyphenols and can exert anti-ferroptotic activity through antioxidant pathways. The antioxidant activity of polyphenols is mainly determined by the number and substitution position of phenolic hydroxyl groups, the type of parent nucleus modification, glycosylation pattern and molecular degree of polymerization. Their structural diversity enables them to directly scavenge reactive oxygen free radicals through hydrogen atom transfer or electron transfer, and also inhibit the Fenton reaction by chelating transition metal ions such as Fe²⁺ to block free radical generation.^128,129

Resveratrol

Resveratrol is a naturally occurring stilbene derivative polyphenol widely found in grapes, berries, and red wine.¹³⁰ It has garnered significant attention for its potential antioxidant, anti-inflammatory, anti-aging, and cardiovascular protective effects.^131,132 Current evidence suggests that resveratrol exhibits definite ferroptosis regulatory activity in sepsis-induced cardiomyopathy. In the CLP-induced rat model of cardiomyopathy, resveratrol treatment significantly improved cardiac function, reduced the levels of myocardial injury markers, and alleviated histopathological damage of myocardial tissues. Resveratrol alleviated LPS-induced injury in H9c2 cardiomyocytes, reduced ROS levels and restored mitochondrial membrane potential. Mechanistic studies revealed that resveratrol upregulated the expression of GPX4 and FTH1, downregulated the expression of ACSL4 and TFR1, reduced iron content and MDA levels in myocardial tissues, increased GSH content, and inhibited lipid peroxidation, thereby alleviating ferroptosis. Molecular docking confirmed that resveratrol has a good binding affinity to SIRT1. The SIRT1 inhibitor EX527 reversed the ameliorating effects of resveratrol on cardiac function, myocardial injury and ferroptosis. These results indicate that resveratrol inhibits ferroptosis by activating the SIRT1/Nrf2 signaling pathway, thereby ameliorating sepsis-induced cardiomyopathy.⁶⁴

Urolithin A

Urolithin A is a gut microbiota metabolite of ellagitannins and ellagic acid in foods such as pomegranates and strawberries, which belongs to polyphenol compounds.¹³³ Urolithin A possesses a variety of pharmacological activities, including antioxidant, anti-inflammatory, anti-aging effects and muscle function improvement.^134,135 In the LPS-induced mouse model of ALI, urolithin A treatment alleviated histopathological damage of lung tissues, reduced the lung wet/dry ratio and BALF protein content, decreased neutrophil infiltration and inflammatory factor release, simultaneously increased antioxidant enzyme activity and reduced MDA levels. In in vitro experiments, urolithin A inhibited the accumulation of ROS and mitochondrial ROS in LPS-stimulated BEAS-2B human bronchial epithelial cells, and reversed abnormalities in ferroptosis-related indicators. Mechanistic studies revealed that urolithin A promoted the degradation of Keap1, activated the nuclear translocation of Nrf2, and upregulated the expression of its downstream targets including HO-1, NQO1, GPX4 and SLC7A11. The Nrf2 inhibitor ML385 reversed the inhibitory effects of urolithin A on inflammation, oxidative stress and ferroptosis, and the ferroptosis inducer erastin also reversed its protective effect. Collectively, urolithin A ameliorates SA-ALI by inhibiting ferroptosis via activation of the Keap1-Nrf2/HO-1 signaling pathway.⁶⁵

TCM Formulations

While monomeric compounds provide precise molecular targets for ferroptosis modulation, the multicomponent nature of traditional Chinese medicine offers distinct advantages through synergistic interactions and network-based regulation. Classical TCM compound formulae, refined through centuries of clinical practice and modern pharmaceutical development, have demonstrated remarkable efficacy in sepsis management by simultaneously targeting multiple pathological processes including ferroptosis, inflammatory cascades, and organ dysfunction. This section examines representative formulae and their modern preparations with particular focus on their mechanistic integration of ferroptosis suppression within the holistic framework of sepsis treatment. These formulations exemplify the translation from traditional compatibility principles to contemporary evidence-based therapeutics, offering unique insights into multi-target intervention strategies against sepsis-induced ferroptosis.

XueBiJing Injection (XBJ Injection)

XueBiJing Injection (XBJ injection) is a Chinese patent medicine approved by the National Medical Products Administration (NMPA) for the adjuvant treatment of sepsis, possessing functions of activating blood circulation, removing blood stasis, clearing heat, and detoxifying.^136–139 Clinically, XBJ has the strongest evidence base. A multicenter double-blind trial (EXIT-SEP, n = 1817) demonstrated that XBJ reduced 28-day mortality versus placebo.¹⁴⁰ Subsequent network meta-analyses confirmed 150 mL/day as the optimal dose for mortality benefit and demonstrated that in SA-AKI, XBJ improved renal function and reduced mortality.^141,142 Modern studies have shown that XBJ injection exerts various pharmacological effects, including anti-inflammatory, anticoagulant, immunomodulatory, vascular endothelial protection, and anti-oxidative stress activities.¹⁴³ In vitro and in vivo experiments showed that XBJ injection reduced the levels of Fe²⁺ and MDA in lung tissues and cells, increased GSH content, upregulated the expression of GPX4, xCT and FTH1, downregulated ACSL4 expression, inhibited ferroptosis in alveolar epithelial cells, and alleviated histopathological damage of lung tissues. Lipidomics analysis revealed that XBJ injection can regulate ferroptosis-related pathways including glycerophospholipid metabolism and phospholipid metabolism.⁶⁶ A recent study found that XBJ injection triggered ferroptosis in CCR2hi pro-inflammatory monocytes via the Nrf2/HO-1 pathway, reduced the infiltration of pro-inflammatory monocytes in the lung, and thereby blocked macrophage polarization towards the M1 phenotype. This mechanism was abolished in Nrf2 knockout mice and reversed by the ferroptosis inhibitor Fer-1.⁶⁷ These results indicate that XBJ injection ameliorates SA-ALI through a dual mechanism of inhibiting ferroptosis in lung epithelial cells and inducing ferroptosis in pro-inflammatory monocytes.

TaoHe ChengQi Decoction (THCQD)

Taohe Chengqi Decoction, a classic traditional Chinese medicine formula, is traditionally used for the treatment of febrile diseases, intestinal obstruction and other conditions.¹⁴⁴ A recent meta-analysis of 16 RCTs (n=1034) showed that THCQD as an adjuvant significantly reduced 28-day mortality, improved inflammatory markers and coagulation in sepsis patients, with no increase in adverse events.¹⁴⁵ THCQD has multiple pharmacological effects such as improving hemorheology, anti-inflammatory, and anti-fibrotic activities.^146–148 In the CLP-induced mouse model of sepsis, THCQD pretreatment improved survival rates, enhanced cardiac function indicators, alleviated myocardial histopathological damage, and reduced serum cardiac troponin T (cTnT), creatine kinase-MB (CK-MB) and LDH levels. In the myocardial cell ferroptosis model induced by RSL3, THCQD alleviated cell injury in a dose-dependent manner. Mechanistically, THCQD promoted the nuclear translocation of Nrf2 by activating the Nrf2 signaling pathway, upregulated GPX4 expression and inhibited TFR1 expression, reduced iron deposition and lipid peroxidation levels in myocardial tissues, and thus suppressed ferroptosis. The above protective effects could be reversed by the Nrf2 inhibitor ML385 and Nrf2 gene knockout, confirming the key regulatory role of the Nrf2 pathway. In conclusion, THCQD ameliorates sepsis-induced cardiac dysfunction by inhibiting cardiomyocyte ferroptosis via activation of the Nrf2 signaling pathway.⁶⁸

Dahuang Gancao Decoction (DHGC)

Dahuang Gancao Decoction (DHGC) is traditionally used for clearing damp-heat toxins and promoting blood circulation, with anti-inflammatory, antioxidant and ferroptosis-inhibitory effects.^149–151 Current studies indicate that in the LPS-induced mouse model of AKI and the HK-2 renal tubular epithelial cell model stimulated by the ferroptosis inducer erastin, DHGC significantly improved renal function, alleviated histopathological damage of renal tubules, and corrected abnormalities in ferroptosis-related biochemical indicators. Mechanistically, high-performance liquid chromatography (HPLC) analysis and molecular docking validation identified rhein as the core component exerting its anti-ferroptotic activity, which binds to sirtuin 3 (SIRT3). DHGC mediated the deacetylation of Nrf2 by activating SIRT3, promoted its nuclear translocation, and upregulated GPX4 expression. This protective effect was abolished in SIRT3 knockout mice and SIRT3 knockdown cells. These results indicate that DHGC inhibits ferroptosis via SIRT3-mediated Nrf2 deacetylation, ameliorating sepsis-associated AKI.⁶⁹

Wenqingyin (WQY)

Wenqingyin (WQY) has the effects of clearing heat and detoxifying, nourishing blood and promoting blood circulation, and is widely used in the clinical treatment of various inflammatory diseases.^152,153 In the LPS-induced mouse model of liver injury, WQY alleviated histopathological damage of liver tissues, reduced serum ALT and AST levels, inhibited the release of inflammatory factors, and reversed abnormalities in ferroptosis-related indicators. WQY inhibited erastin-induced ferroptosis in LO2 hepatocytes, reduced the accumulation of ROS and MDA, and restored mitochondrial membrane potential. Mechanistic studies confirmed via SPR assay that berberine, its active component, can directly bind to Nrf2. WQY upregulated the expression of its downstream targets HO-1, GPX4, SLC7A11 and FSP1 by activating the Nrf2 signaling pathway. Both the Nrf2 inhibitor ML385 and Nrf2 gene knockout could reverse the anti-ferroptotic effect of WQY. These results indicate that WQY improves sepsis-induced liver injury by inhibiting hepatocyte ferroptosis via activation of the Nrf2 signaling pathway.⁷⁰

QiShen YiQi Pill (QSYQ)

Qishen Yiqi Pill (QSYQ) is derived from a classic TCM formula, with the effect of replenishing Qi and promoting blood circulation.¹⁵⁴ Modern studies have shown that QSYQ exerts various pharmacological effects, including anti-inflammatory, anti-oxidative stress, and improvement of energy metabolism, demonstrating protective effects in respiratory diseases.^155,156 In the CLP-induced mouse model of sepsis, QSYQ pretreatment reduced the levels of inflammatory factors in serum and BALF, alleviated histopathological damage of lung tissues, decreased the lung wet/dry ratio and Evans blue leakage, upregulated the expression of zonula occludens-1 (ZO-1) and occludin, and improved pulmonary vascular endothelial barrier function. QSYQ-containing serum alleviated hy926 cell death induced by conditioned medium from LPS-stimulated macrophages, reduced endothelial cell death, and improved barrier function and oxidative stress. Network pharmacology analysis identified 127 potential targets of QSYQ in the regulation of sepsis, which were enriched in the advanced glycation end product-receptor for advanced glycation end product (AGE-RAGE) signaling pathway, with cyclooxygenase-2 (COX2) being one of its key targets. QSYQ inhibited RAGE and COX2 expression, upregulated GPX4 and SLC7A11, alleviated endothelial cell ferroptosis and oxidative stress, thereby improving SA-ALI.⁷¹

YiQiFuMai Injection (YQFM)

YiQiFuMai Injection (YQFM) possesses the functions of supplementing Qi, nourishing Yin, restoring pulse, and relieving collapse, and is widely used to treat cardiovascular diseases such as coronary heart disease and heart failure.^157,158 Clinically, a Bayesian network meta-analysis of 77 RCTs (n=5647) in septic shock ranked YQFM combined with conventional Western medicine may be superior to Western medicine alone in the treatment of septic shock, with a favorable safety profile.¹⁵⁹ Recent research has demonstrated that YQFM exerts a significant protective effect against sepsis-induced cardiomyopathy. In the CLP-induced rat model of cardiomyopathy, YQFM increased the survival rate, reduced serum levels of cTnI, CK-MB and LDH, and alleviated histopathological damage of myocardial tissues. In in vitro experiments, YQFM alleviated LPS-induced injury in H9c2 cardiomyocytes and reversed abnormalities in ferroptosis-related indicators. Mechanistic studies revealed that YQFM upregulated the expression of SLC7A11, solute carrier family 3 member 2 (SLC3A2) and GPX4, and activated the xCT/GPX4 axis. These results indicate that YiQiFuMai injection improves sepsis-induced cardiomyopathy by inhibiting ferroptosis via activation of the xCT/GPX4 axis.⁷²

Advances in Drug Delivery Systems for Bioactive Natural Products in Sepsis Therapy

Despite the promising anti-ferroptotic and organ-protective activities of numerous natural products and TCM-derived compounds, their clinical translation in sepsis is often hindered by inherent physicochemical and biopharmaceutical limitations, including poor aqueous solubility, low oral bioavailability, rapid metabolic clearance, and insufficient tissue targeting. To overcome these hurdles, a spectrum of advanced drug delivery systems has been engineered to enhance the therapeutic performance of these bioactive agents.

Liposomes represent the most extensively investigated and clinically mature nanocarrier platform, particularly suitable for improving the oral bioavailability and pulmonary deposition of natural products. Quercetin-loaded liposomes addressed these limitations, attenuated pulmonary inflammation, and reduced mortality in LPS-induced septic mice.¹⁶⁰ A novel nebulized baicalein-phospholipid complex liposome (BAPC-DLP) improved baicalein’s solubility, bioavailability and pulmonary deposition, and attenuated LPS-induced ALI.¹⁶¹ Nasal-delivered andrographolide liposomes (AGP-Lip) with strong mucoadhesive properties ameliorated TNF-α-induced acute pulmonary inflammation by suppressing the NF-κB pathway and proinflammatory cytokine expression.¹⁶² Two oral dihydroartemisinin-loaded nanoliposomal systems, cRGD-polydopamine functionalized cRPNLs and 2-monoacylglycerol-mimetic SER-LPs, were constructed to reduce the hepatic first-pass effect and markedly improve oral bioavailability via stimulus-responsive release or intestinal lymphatic transport.^163,164

Besides liposomes, a variety of bilayer-free nanoparticles have been developed, featuring high drug-loading capacity, multi-functional integration, and the capacity to cross biological barriers such as the blood-brain barrier. Macrophage membrane-coated quercetin-tannic acid biomimetic nanomodulator (mAOI NP) targeted inflammatory sites, penetrated the blood-brain barrier, alleviated SAE, and improved survival.¹⁶⁵ PEI-modified ginsenoside Rb1 self-assembled nanoparticles (GRb1@PEI) with enhanced macrophage targeting attenuated sepsis-associated acute lung injury via inhibiting the TNF-α pathway and served as multifunctional antibiotic delivery nanocarriers.¹⁶⁶ pH-triggered tryptamine-cinnamaldehyde/fisetin self-assembled nanodrugs penetrated the blood-brain barrier and exerted combined antioxidative, anti-inflammatory and antibacterial activities for targeted SAE therapy.¹⁶⁷ Orally administered resveratrol-loaded lipid-core nanocapsules (RSV-LNCs) enhanced pulmonary accumulation and bioavailability, and attenuated LPS-induced acute lung injury by inhibiting the ERK and PI3K/Akt pathways.¹⁶⁸

Collectively, these advanced delivery technologies represent a critical translational bridge that potentiates the therapeutic potential of natural products in sepsis.

Discussion

Sepsis is a complex systemic inflammatory response syndrome, and universally effective pharmacological therapies remain clinically elusive. Ferroptosis has been increasingly recognized as a critical driver in the pathological progression of sepsis, providing a highly promising therapeutic target. In recent years, research on the therapeutic potential of natural products targeting ferroptosis in sepsis has been steadily increasing. Diverse natural products, including flavonoids, terpenoids, alkaloids, polyphenolic compounds, and classical Traditional Chinese Medicine (TCM) formulas, have demonstrated profound cytoprotective effects against sepsis-induced multiorgan dysfunction. Collectively, these agents exert systemic anti-ferroptotic effects by targeting multiple nodes in the ferroptosis regulatory network. Importantly, targeting ferroptosis in sepsis may not be equated with universal ferroptosis suppression. As demonstrated by the dual action of XueBiJing injection, selectively inducing ferroptosis in pro-inflammatory immune cells while inhibiting it in parenchymal cells can simultaneously rebalance immune homeostasis and preserve organ integrity.

Various active ingredients and compound formulations from traditional Chinese medicine intervene in sepsis-induced ferroptosis at three levels, namely antioxidant defense, transcriptional cascade regulation, and cross-regulation between inflammation and ferroptosis, by targeting the three core signaling pathways GPX4-GSH, Keap1-Nrf2 and NF-κB. Concurrently, upstream iron metabolism modulators such as quercetin and ginsenoside Rb1 and downstream lipid peroxidation inhibitors such as dihydroartemisinin and tetramethylpyrazine form a bidirectional synergistic network, jointly blocking the positive feedback loop between iron metabolism dysregulation and lipid peroxidation, thereby providing a multi-target integrated strategy for the treatment of sepsis. The regulatory mechanisms of natural products against ferroptosis in sepsis are illustrated in Figure 2.

Figure 2.

The regulatory mechanisms of natural products against ferroptosis in sepsis.

From a mechanistic standpoint, the body of evidence covered in this review can be broadly divided into three progressive stages of investigation. The first is phenotypic confirmation, which establishes a preliminary association between natural product intervention, modulation of ferroptosis pathways, and organ protection in cellular or animal sepsis models. The second is causal pathway validation, wherein pharmacological inhibitors or genetic manipulations are employed to verify that specific signaling pathways are indispensable for the ferroptosis-regulating effects of natural products. Most existing studies in this field have reached this stage. The third is direct target identification, which adopts biophysical assays including SPR and MST combined with site-specific mutagenesis to confirm direct binding between compounds and target proteins. Only a small number of compounds have been characterized with this depth of mechanistic resolution. Aligned with this staged progression, the field as a whole remains in the early and intermediate phases of mechanistic elucidation.

Despite these preliminary advances, three core limitations persist that severely hinder the clinical translation of natural product-based ferroptosis-targeted therapies. First, mechanistic inconsistencies persist across available evidence. The regulatory role of HO-1 shows divergent findings: both its inhibition and upregulation have been linked to ferroptosis-related protection, depending on dosage and disease stage. Meanwhile, while Nrf2 activation consistently alleviates acute organ injury in sepsis, its long-term impact on immune recovery during the late immunosuppressive stage has not been fully clarified, and its effects vary across different cell types. Furthermore, most work focuses on ferroptosis modulation in parenchymal cells, whereas the overall impact of regulating immune cell ferroptosis in sepsis remains poorly clarified. Second, study findings have limited generalizability due to overreliance on single experimental models. Several representative compounds show reproducible effects across both LPS and CLP sepsis models and corresponding cellular systems. Nevertheless, most studies rely on a single experimental model, mostly LPS stimulation. The pathophysiological gap between endotoxemia and polymicrobial sepsis means the generalizability of these findings still needs verification across more disease-relevant models. Third, unfavorable pharmacokinetic profiles constitute a major translational bottleneck. The clinical translation of preclinical findings is hampered by inherent drawbacks of natural compounds, including poor solubility, low bioavailability, metabolic instability, and inadequate target tissue distribution.

To address these pharmacokinetic hurdles, nanoparticle drug delivery systems including polymeric nanoparticles, liposomal formulations, and melanin nanoparticles have been extensively investigated in preclinical sepsis studies. These delivery strategies improve aqueous solubility, prolong systemic circulation time, and enhance targeted accumulation of natural products in injured organs, offering a tangible path to bridge preclinical efficacy and clinical application. Notably, several classical TCM formulations have already entered clinical trials for sepsis management and have shown favorable therapeutic outcomes, with available clinical data suggesting no significant increase in serious adverse events.

Conclusion and Perspectives

In summary, this review delineates the protective effects of natural products against sepsis-induced ferroptosis through multi-level, multi-target mechanisms. Future efforts should concern direct target identification via advanced biophysical techniques, multi-omics integration for dynamic network construction, and optimization of drug delivery systems to overcome pharmacokinetic barriers. In the future, with a deeper understanding of ferroptosis-dependent regulatory mechanisms and the continuous advancement of targeted drug delivery systems, natural products are expected to become an important pharmacological strategy in the treatment of sepsis.

Funding Statement

This work was supported by The Natural Science Foundation of Chongqing (No. CSTB2024NSCQ-MSX0315), Scientific and Technological Research Program of Chongqing Municipal Education Commission (No. KJQN202600468), The Third Affiliated Hospital of Chongqing Medical University Project (No. KY23046, KY23042), The Chongqing Key Specialty Construction Project in Clinical Pharmacy, and The Chongqing Yubei District Clinical Key Specialty Construction Project.

Abbreviations

AEC2s, alveolar type II epithelial cells; AGE-RAGE, advanced glycation end product – receptor for advanced glycation end product; AGP-Lip, andrographolide liposomes; AKT, protein kinase B; ALI, acute lung injury; ALOX15, arachidonate-15-lipoxygenase; ALOX5, arachidonate 5-lipoxygenase; ALT, alanine aminotransferase; ARE, antioxidant response element; AST, aspartate aminotransferase; Atf3, activating transcription factor 3; BALF, bronchoalveolar lavage fluid; BAPC-DLP, baicalein-phospholipid complex liposome; BUN, blood urea nitrogen; CLP, cecal ligation and puncture; COX2, cyclooxygenase-2; Cr, creatinine; DAMPs, damage-associated molecular patterns; DHA, dihydroartemisinin; DHGC, Dahuang Gancao Decoction; DMOG, dimethyloxalylglycine; EF, ejection fraction; Fer-1, ferrostatin-1; FPN, ferroportin 1; FS, fractional shortening; FSP1, ferroptosis suppressor protein 1; FTH1, ferritin heavy chain 1; FTL, ferritin light chain; GM-CSF, granulocyte-macrophage colony-stimulating factor; GPX4, glutathione peroxidase 4; GRb1@PEI, ginsenoside Rb1 self-assembled nanoparticles; GSH, glutathione; GSK3β, glycogen synthase kinase 3β; HIF-1α/HIF1A, hypoxia-inducible factor 1-alpha; HMGB1, high mobility group box 1; HMOX1, heme oxygenase 1; HO-1, heme oxygenase-1; HPLC, high-performance liquid chromatography; IFA, isoferulic acid; IL-7, interleukin-7; IRAK4, interleukin-1 receptor-associated kinase 4; IκBα, inhibitor of NF-κB alpha; Keap1, Kelch-like ECH-associated protein 1; LDH, lactate dehydrogenase; LPS, lipopolysaccharide; LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter; mAOI NP, Macrophage membrane-coated quercetin-tannic acid biomimetic nanomodulator; MAPK, mitogen-activated protein kinase; MDA, malondialdehyde; MPO, myeloperoxidase; MST, microscale thermophoresis; NF-κB, nuclear factor-kappa B; NLRP3, NOD-like receptor family pyrin domain containing 3; NMPA, National Medical Products Administration; NQO1, NAD(P)H quinone dehydrogenase 1; Nrf2, nuclear factor erythroid 2-related factor 2; PSS, post-sepsis syndrome; PD-1/PD-L1, programmed cell death protein 1/programmed death-ligand 1; PI3K, phosphatidylinositol 3-kinase; PL-PUFAs, polyunsaturated fatty acid phospholipids; PTGS2, prostaglandin-endoperoxide synthase 2; PUFAs, polyunsaturated fatty acids; QSYQ, QiShenYiQi Pill; ROS, reactive oxygen species; RSV-LNCs, resveratrol-loaded lipid-core nanocapsules; SAE, sepsis-associated encephalopathy; SA-AKI, sepsis-associated acute kidney injury; SA-ALI, sepsis-associated acute lung injury; scRNA-seq, single-cell RNA sequencing; SIRT1, sirtuin 1; SIRT3, sirtuin 3; SLC3A2, solute carrier family 3 member 2; SLC7A11, solute carrier family 7 member 11; SPR, surface plasmon resonance; STEAP3, six-transmembrane epithelial antigen of prostate 3; System Xc⁻, cystine/glutamate antiporter system Xc⁻; TCM, traditional Chinese medicine; TFR1, transferrin receptor 1; THCQD, TaoHe ChengQi Decoction; TLR4, toll-like receptor 4; TLRs, Toll-like receptors; TMP, tetramethylpyrazine; WQY, Wenqingyin; XBJ, XueBiJing; xCT, solute carrier family 7 member 11 (SLC7A11); YQFM, YiQiFuMai Injection; Znpp, zinc protoporphyrin; ZO-1, zonula occludens-1; 4-HNE, 4-hydroxynonenal; 15-HETE, 15-hydroxyeicosatetraenoic acid; 15-HpETE, 15-hydroperoxyeicosatetraenoic acid.

Data Sharing Statement

Data sharing is not applicable to this article as no data were created or analyzed in this study.

Author Contributions

FW: Conceptualization, Writing original draft, Data curation and Visualization. CG: Conceptualization, Writing original draft, Data curation, Visualization. XZ: Conceptualization, Writing review and editing, Data curation, Visualization. TL: Writing review and editing, Data curation, Visualization. XL: Writing review and editing, Data curation. QD and WL: Funding acquisition, Supervision, Writing review and editing, Data curation. All authors 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.