Ferroptosis inhibitors: mechanisms of action and therapeutic potential

Abstract

Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation. It plays a crucial role in various pathological conditions, including neurodegenerative diseases, cancer, ischemia–reperfusion injury, and organ failure. This review systematically explores the key mechanisms underlying ferroptosis, including polyunsaturated fatty acid-containing phospholipid (PUFA-PL) peroxidation, iron metabolism, and mitochondrial dysfunction. Additionally, we summarize major endogenous ferroptosis defense systems, including the SLC7A11-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis, the ferroptosis suppressor protein 1 (FSP1)-ubiquinol (CoQH₂) system, the mitochondrial dihydroorotate dehydrogenase (DHODH)-CoQH₂ pathway, and the guanosine triphosphate cyclohydrolase 1 (GCH1)-tetrahydrobiopterin (BH4) pathway, which act as critical brakes on ferroptosis. Furthermore, we discuss various small-molecule inhibitors targeting ferroptosis, categorized by their mechanisms of action, including iron chelators, lipid peroxidation inhibitors, antioxidants, and regulatory pathway modulators. Recent advances in pharmacological strategies and their potential therapeutic applications are also highlighted.

Introduction

Ferroptosis is a regulated form of cell death characterized by the iron-dependent accumulation of lipid peroxides within cellular membrane [1]. Mechanistically, cells undergo ferroptosis when antioxidant defense systems—most prominently glutathione peroxidase 4 (GPX4) —fail to detoxify lipid peroxyl radicals, leading to uncontrolled lipid peroxidation, membrane damage, and collapse of redox balance. Morphologically, ferroptosis is characterized by unique ultrastructural features, including shrunken mitochondria with increased membrane density, reduced or absent cristae, and rupture of the outer mitochondrial membrane, while nuclear morphology remains largely preserved. Although it shares similarities with necrotic cell death, such as plasma membrane rupture, ferroptosis is mechanistically defined as a non-apoptotic pathway distinct from classical necrosis and autophagy. Its execution can be specifically prevented by inhibitors of lipid peroxidation, including ferrostatin-1 and liproxstatin-1 [1].

Since its identification in 2012, ferroptosis has emerged as a key player in a wide spectrum of pathological conditions, including neurodegenerative diseases, ischemia–reperfusion injury, metabolic disorders, and malignancies [2, 3]. This metabolic vulnerability makes ferroptosis not only a major driver of tissue damage, but also a promising therapeutic target in diseases characterized by oxidative stress or therapy resistance [4, 5].

Importantly, ferroptosis is tightly regulated by multiple intrinsic defense systems that counteract lipid peroxidation and maintain cellular integrity. Beyond the canonical GPX4-glutathione (GSH) axis, recent studies have identified additional protective mechanisms such as ferroptosis suppressor protein 1 (FSP1), guanosine triphosphate cyclohydrolase 1 (GCH1), and mitochondrial dihydroorotate dehydrogenase (DHODH), which provide complementary safeguards against ferroptotic death. The complexity and redundancy of these pathways underscore the need to better define their relative contributions across different cell types and disease contexts [6, 7].

Given its involvement in various pathologies, pharmacological modulation of ferroptosis has become an attractive therapeutic strategy. Small molecule inhibitors have been extensively explored as potential agents to suppress ferroptosis in conditions where oxidative damage exacerbates disease progression, such as neurodegeneration, acute kidney injury (AKI), and cardiovascular disease [8, 9]. These inhibitors can be broadly categorized based on their mechanisms of action, including iron chelators that limit the availability of redox-active iron, lipid peroxidation inhibitors that suppress oxidative stress, and activators of endogenous antioxidant pathways such as nuclear factor erythroid 2‑related factor 2 (NRF2) and GPX4 stabilization [10].

This review provides a comprehensive analysis of ferroptosis, focusing on its molecular underpinnings, regulatory networks, and opportunities for therapeutic modulation. The following sections outline the principal processes driving ferroptosis, including iron metabolism, oxidative stress, and mitochondrial regulation. Endogenous defense pathways that counteract ferroptosis are subsequently examined, with a focus on their redundancy and context-specific activity. Recent advances in small-molecule inhibitors are then highlighted, addressing their mechanisms of action, pharmacological potential, and challenges in clinical application. Collectively, this review integrates current knowledge of ferroptosis drivers and suppressors to inform future therapeutic strategies in human diseases.

The engines of ferroptosis

Ferroptosis is a form of regulated cell death driven by the iron-catalyzed peroxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids (PUFA-PLs). When lipid peroxidation surpasses the capacity of ferroptosis defense mechanisms, oxidative damage leads to membrane rupture and subsequent cell death. The principal drivers of ferroptosis include PUFA-PL synthesis and peroxidation, iron metabolism, and mitochondrial metabolism. Clarifying these processes is essential for understanding the regulatory network of ferroptosis and identifying potential therapeutic targets (Fig. 1).

Fig. 1.

The molecular mechanism of ferroptosis. Reactive oxygen species (ROS) accumulation triggers ferroptosis, a form of regulated cell death characterized by membrane damage through lipid peroxidation. The biosynthesis of polyunsaturated fatty acid-containing phospholipids (PUFA-PLs) requires two key enzymes: ACSL4 activates free PUFAs to form PUFA-CoAs, while LPCAT3 catalyzes the incorporation of PUFA-CoAs into membrane phospholipids. These PUFA-PLs are subsequently oxidized through lipoxygenase (LOX)-catalyzed enzymatic reactions, initiating lipid peroxidation cascades. Iron metabolism critically regulates ferroptosis via three coordinated processes: (1) TFR1-mediated Fe³⁺ uptake, (2) STEAP3-dependent reduction of Fe³⁺ to Fe²⁺, and (3) DMT1-facilitated Fe²⁺ transport. This iron flux elevates the labile iron pool (LIP), thereby promoting Fenton reactions that amplify ROS production. Mitochondrial contributions to ferroptosis involve glutaminolysis, wherein glutamine (Gln) is converted to glutamate (Glu) and subsequently to α-ketoglutarate (α-KG) to fuel the TCA cycle. This metabolic reprogramming sustains oxidative phosphorylation, resulting in electron leakage from the ETC and consequent ROS accumulation. There are at least three antioxidant systems that counteract ferroptosis: (1) SLC7A11-GSH-GPX4 axis: System Xc⁻ imports cystine for glutathione (GSH) biosynthesis, enabling GPX4 to reduce lipid hydroperoxides. (2) FSP1-CoQH₂ system: Independent of GPX4, FSP1 regenerates reduced ubiquinol (CoQH₂) to neutralize lipid radicals. (3) Mitochondrial DHODH pathway: Dihydroorotate dehydrogenase (DHODH) maintains CoQH₂ levels in the inner mitochondrial membrane, protecting against lipid peroxidation

PUFA-PL synthesis and peroxidation

PUFA-PLs serve as the critical substrates in ferroptosis, as their oxidative modification destabilizes membranes and precipitates cell death. Unlike saturated and monounsaturated fatty acids, PUFAs, such as arachidonic acid (AA) and adrenic acid (AdA), contain multiple double bonds, making them highly susceptible to peroxidation [11]. Prior to oxidation, PUFAs must undergo enzymatic activation and incorporation into membrane phospholipids. Acyl-CoA synthetase long-chain family member 4 (ACSL4) converts free PUFAs into acyl-CoA derivatives (PUFA-CoAs), which are subsequently esterified into lysophosphatidylcholine acyltransferase 3 (LPCAT3) [12, 13]. This process generates PUFA-PLs that are embedded in membranes and become the direct targets of oxidative attack. Lipid peroxidation of PUFA-PLs is initiated primarily by reactive oxygen species (ROS).

A major contributor is iron-dependent Fenton chemistry, in which ferrous iron (Fe²⁺) reacts with hydrogen peroxide to generate hydroxyl radicals capable of oxidizing PUFA-PLs into lipid peroxides (PUFA-OOH) [14]. The accumulation of PUFA-OOH disrupts membrane architecture, enhances permeability, and yields reactive aldehydes such as 4-hydroxynonenal (4-HNE) and 4-hydroxyhexenal (4-HHE), all of which intensify cellular injury. In addition to non-enzymatic reactions, enzymatic peroxidation catalyzed by lipoxygenases (LOXs) amplifies lipid oxidative generation [15]. These processes highlight the dual contribution of enzymatic and non-enzymatic pathways to ferroptosis in a context-dependent manner (Fig. 1).

Iron metabolism

Iron is indispensable for numerous physiological processes, yet its redox activity makes it a potent catalyst of ferroptosis. Ferric iron (Fe³⁺), transported in complex with transferrin, is internalized via transferrin receptor (TFR1) and reduced to Fe²⁺ by the metalloreductase STEAP3 within endosomes [16]. Fe²⁺ subsequently enters the cytosolic labile iron pool (LIP) through divalent metal transporter 1 (DMT1) and other non-transferrin-bound iron (NTBI) carriers [17]. When excessive, Fe²⁺ fuels Fenton chemistry and escalates ROS production, thereby amplifying lipid peroxidation and ferroptosis.

Intracellular iron balance is safeguarded by ferritin, which sequesters excess iron, and ferroportin (FPN), the sole known iron exporter. Ferritin degradation via NCOA4-mediated ferritinophagy releases stored iron into the LIP, whereas FPN mediates iron efflux but is negatively regulated by hepcidin. Disruption of these pathways, through enhanced uptake, excessive ferritin degradation, or reduced FPN activity, elevates intracellular Fe²⁺ levels and drives ferroptotic susceptibility.

Mitochondrial metabolism

ROS generation from the electron transport chain

Mitochondria are the primary source of intracellular reactive oxygen species (ROS), mainly derived from electron leakage within the electron transport chain (ETC). Under physiological conditions, electrons transferred through Complexes I and III occasionally escape and react with molecular oxygen, producing superoxide anions (O₂•⁻). These are subsequently converted by superoxide dismutase (SOD) into hydrogen peroxide (H₂O₂), which can further react with ferrous iron (Fe²⁺) via the Fenton reaction to generate highly reactive hydroxyl radicals (•OH). Excessive ROS accumulation damages mitochondrial membranes, proteins, and lipids, ultimately driving ferroptotic cell death. Thus, ETC leakage represents a central mechanism linking mitochondrial activity to oxidative stress and ferroptosis.

metabolic regulation: glutamine catabolism and AMPK-ACC axis

In addition to ROS generation, mitochondrial metabolism influences ferroptosis through nutrient decomposition and metabolic signaling pathways. Glutamine decomposition supplies α-ketoglutarate into the tricarboxylic acid (TCA) cycle, fueling mitochondrial respiration and supporting lipid biosynthesis. Enhanced glutamine catabolism not only sustains energy production but also increases the availability of substrates for PUFA-PL synthesis, thereby sensitizing cells to lipid peroxidation. The AMPK–ACC axis further regulates lipid metabolism in ferroptosis. Activation of AMP-activated protein kinase (AMPK) under energy stress conditions inhibits acetyl-CoA carboxylase (ACC), reducing fatty acid biosynthesis and limiting PUFA-PL incorporation into membranes. This metabolic checkpoint thus acts as a protective mechanism against ferroptosis by lowering the supply of oxidizable lipid substrates. Importantly, mitochondrial iron accumulation has emerged as another key determinant of ferroptotic sensitivity. Iron is indispensable for TCA cycle enzymes and ETC complexes; however, disruption of mitochondrial iron homeostasis enlarges the labile iron pool (LIP), intensifying ROS production through iron-catalyzed reactions. Insufficient sequestration by ferritin or impaired iron export via FPN promotes mitochondrial iron overload, exacerbating lipid peroxidation and reinforcing ferroptosis progression.

Non-GPX4 defense systems: FSP1–CoQ10 vs DHODH–CoQH₂

Recent advances have identified FSP1–CoQ10 and DHODH–CoQH₂ as critical non-GPX4 defense systems that broaden the landscape of ferroptosis regulation. Ferroptosis suppressor protein 1 (FSP1) (also known as AIFM2) localizes to cellular membranes in a myristoylation-dependent manner, where it reduces ubiquinone (CoQ10) to ubiquinol (CoQH₂) using NAD(P)H, thereby generating a potent radical-trapping antioxidant pool that suppresses lipid peroxidation outside mitochondria. In contrast, DHODH is anchored within the inner mitochondrial membrane and couples the oxidation of dihydroorotate to orotate with CoQ reduction, producing a localized reservoir of CoQH₂ that specifically protects mitochondrial membranes from ferroptotic damage. While these two pathways act in distinct cellular compartments, they function in a complementary rather than redundant manner, collectively safeguarding membrane integrity when GPX4 activity is compromised. Their therapeutic potential is context-dependent: augmentation of FSP1 activity or CoQ10 supplementation may benefit diseases characterized by widespread membrane lipid peroxidation, whereas enhancing DHODH function may be particularly relevant in mitochondria-rich, OXPHOS-active tissues vulnerable to ischemia–reperfusion injury or neurodegeneration. Conversely, pharmacological inhibition of FSP1 or DHODH can sensitize tumors to ferroptosis, especially in cancers with high FSP1 expression or reliance on mitochondrial metabolism, raising the possibility of synthetic lethality when combined with GPX4 inhibition. Nevertheless, unresolved issues remain, including the extent to which these systems compensate for GPX4 loss, the influence of CoQ biosynthetic capacity on their effectiveness, and the role of mitochondrial iron and ROS in amplifying lipid peroxidation. Furthermore, translational challenges such as tissue targeting (e.g., blood–brain barrier penetration), metabolic stability (e.g., optimization of CoQ analogs), and the need for predictive biomarkers underscore the importance of continued mechanistic studies to refine therapeutic strategies exploiting these emerging ferroptosis defense nodes.

The brakes of ferroptosis

Ferroptosis is regulated by multiple endogenous defense mechanisms that counteract lipid peroxidation and maintain redox homeostasis. These protective mechanisms mitigate oxidative stress, safeguard membrane integrity, and ultimately determine cellular susceptibility to ferroptotic death. The major ferroptosis defense systems include the SLC7A11-GSH-GPX4 axis, the FSP1-CoQH₂ system, the DHODH-CoQH₂ pathway, and the GCH1-BH4 pathway. These networks serve as crucial “brakes” on ferroptosis and illustrate the complexity of its regulation.

The SLC7A11-GSH-GPX4 axis

The SLC7A11-GSH-GPX4 axis constitutes the canonical defense against ferroptosis. SLC7A11 (also known as xCT) is a component of the cystine/glutamate antiporter system (system xₙ⁻) that imports cystine in exchange for glutamate [18]. Intracellular cystine is rapidly reduced to cysteine via an NADPH-dependent manner, providing the precursor for GSH biosynthesis [19].

GSH is a major cofactor for GPX4, a selenium-dependent enzyme that reduces lipid hydroperoxides (PUFA-PL-OOH) to their corresponding non-toxic lipid alcohols (PUFA-PL-OH), thereby preventing membrane destabilization [20]. During this process, GSH is oxidized to glutathione disulfide (GSSG), which is subsequently recycled back to GSH by glutathione reductase (GR) in an NADPH-dependent manner [21]. The SLC7A11-GSH-GPX4 System is considered the central gatekeeper of ferroptosis, and its pharmacological regulation has been a key focus in ferroptosis-related research.

The FSP1–CoQH2 system

CoQ10 is a lipophilic antioxidant that plays a key role in preventing membrane lipid peroxidation. FSP1 functions independently of GPX4 to maintain ferroptosis resistance [22–24]. FSP1 is localized predominantly to the plasma membrane but can also translocate to mitochondria. Through N-myristoylation, FSP1 anchors to membrane surfaces, where it catalyzes the NAD(P)H-dependent reduction of CoQ10 to CoQH₂. CoQH₂ acts as a potent radical-trapping antioxidant that directly scavenges lipid peroxyl radicals, thereby attenuating lipid peroxidation and ferroptosis [9]. Additionally, CoQH₂ supports the regeneration of α-tocopherol (vitamin E), further enhancing cellular antioxidant capacity. Therefore, the FSP-CoQH₂ system represents an essential parallel defense mechanism that complements GPX4 activity.

The DHODH–CoQH₂ system

The DHODH-CoQH₂ system, an inner mitochondrial membrane enzyme required for pyrimidine biosynthesis, has recently been identified as a mitochondria-specific ferroptosis defense factor [25]. DHODH catalyzes the oxidation of dihydroorotate (DHO) to orotate, utilizing CoQ10 as an electron acceptor. This reaction generates mitochondrial CoQH₂, which locally suppresses lipid peroxidation and protects against ferroptosis [25].

When GPX4 is inactivated, DHODH activity becomes increasingly critical for maintaining mitochondrial redox stability. Elevated CoQH₂ in this context enhances lipid peroxyl radical scavenging and restricts ferroptotic progression. However, simultaneous inhibition of GPX4 and DHODH abolishes this protective capacity, resulting in profound mitochondrial lipid peroxidation and extensive ferroptotic cell death.

The GCH1–BH4 system

The GCH1–BH4 pathway has been identified as an alternative ferroptosis defense mechanism independent of GPX4 and CoQH₂ [26, 27]. GCH1 catalyzes the rate-limiting step in the biosynthesis of BH4. BH4 acts as a radical-trapping antioxidant that directly neutralizes lipid peroxyl radicals and stabilizes membranes against oxidative damage. Cells with high GCH1 expression or enhanced BH4 biosynthesis show increased resistance to ferroptosis.

Beyond its direct antioxidant effects, BH4 contributes to redox regulation by supporting CoQ10 biosynthesis through the production of 4-hydroxybenzoate, a precursor in CoQ10 synthesis [26, 28]. Additionally, dihydrofolate reductase (DHFR) is required for the regeneration of BH4 from its oxidized form, dihydrobiopterin (BH2). Inhibition of DHFR depletes BH4 levels and enhances ferroptotic sensitivity, further underscoring its importance in ferroptosis resistance [29].

Small molecule inhibitors targeting ferroptosis

Pharmacological modulation of ferroptosis has attracted substantial interest as a therapeutic strategy across cancer, neurodegeneration, and ischemic injury. Small-molecule inhibitors at multiple nodes of the ferroptotic network, primarily by altering iron metabolism, suppressing lipid peroxidation, or reinforcing antioxidant defense systems (Table 1).

Table 1.

Summary of ferroptosis inhibitors

Category	Inhibitor	Mechanism	Disease	References
Iron metabolism	Deferoxamine (DFO)	Iron chelator	SCI	[30]
	Deferiprone (DFP)	Iron chelator	Multiple sclerosis	[31]
	Deferasirox (DFX)	Iron chelator	Ulcerative colitis	[32]
	CN128	Iron chelator	β-thalassemia	[35]
	DFA1	Iron chelator	-	[36]
	Compound 9c	Iron chelator; Scavenges free radicals	AKI	[31]
	Dexrazoxane (DXZ)	Iron chelator; upregulates GPX4, FTH1	Cardiomyopathies	[37]
	2,2′-bipyridine	Iron chelator	-	[9]
	Phenanthroline	Iron chelator	-	[9]
	M-30	Iron chelator	AD	[38]
	Baicalein	Iron chelator; upregulates GPX4 and GSH	-	[39]
	Hinokitiol	Iron chelator; activates Nrf2; upregulates SLC7A11, GPX4, HO-1	Parkinson’s disease	[40]
	Tannins (TA)	Iron chelator	Iron overload	[41]
	BMS536924	Iron chelator	-	[42]
	Thymosin β4	Iron chelator; upregulates BAX, HO-1 and HSP70	-	[43]
	Ciclopirox (CPX)	Iron chelator	Neurological disorders	[45]
	AKI-02	Iron chelator	AKI	[44]
	YL-939	Binds 2PHB2; upregulates ferritin; reduces iron	Liver injury	[8]
	Compound 9a	Stabilizes Fe2⁺ levels	IS	[46]
	NSC306711	Blocks Tf-TfR pathway; inhibits iron uptake	-	[47]
	Pyrrolidine dithiocarbamate (PDTC)	Inhibits DMT1	-	[48]
	Benzylisothiourea	Inhibits DMT1	-	[49]
	Carthamin yellow (CY)	Inhibits Fe2+ and ROS; reverses ACSL4, TFR1, GPX4, FTH1	MIRI	[50]
	Farrerol (FA)	Reduces lipid peroxidation	Hypoxic-ischemic encephalopathy	[51]
Lipid metabolism	Vitamin E- α-tocopherol	Scavenges free radicals	Epilepsy	[52]
	Melatonin (MLT)	Scavenges free radicals; activates Nrf2/HO-1	Subarachnoid hemorrhage	[53]
	Vitamin K1 (VK1)	Scavenges free radicals	AKI	[54]
	Menaquinone-4 (MK-4)	Scavenges free radicals; inhibits p53/SLC7A11	Sepsis-associated acute lung injury	[55]
	Trolox	Ameliorates oxygenated PE	NASH	[56]
	Ferrostatin-1 (Fer-1)	Scavenges free radicals	IS	[57]
	SRS11-92	Scavenges free radicals via activating Nrf2	IS	[59]
	UAMC-3203 UAMC-2418	Scavenges free radicals	-	[60]
	Liproxstatin-1 (Lip-1)	Inhibits lipid peroxidation	Ferroptosis-induced cardiovascular disease	[61]
	Lip-2	Upregulates GPX4	Lupus nephritis	[62]
	Compound 51	Scavenges free radicals	IS	[57]
	Compound 7 J	Scavenges free radicals	DOX-induced cardiomyopathy	[63]
	Edaravone (EDA)	Activates Nrf2-FPN; upregulates GPX4	IS, CIRI	[64]
	Olanzapine (OLZ)	Scavenges free radicals	-	[65]
	XJB-5–131	Scavenges free radicals	Renal I/R injury, osteoarthritis	[66]
	JP4-039	Scavenges free radicals	-	[66]
	(S)−6c	Scavenges free radicals	-	[67]
	CuATSM	Scavenges free radicals	IS	[68]
	Compound 25	Scavenges free radicals	-	[69]
	Zileuton	Inhibits LOX-5 and lipid peroxidation	Acute retinal damage	[74]
	MK-886	Inhibits ALOX-5	MIRI	[71]
	BWA4C	Inhibits ALOX-5	Inflammatory bowel diseases	[72]
	PD146176	Inhibits ALOX-5 and lipid peroxidation	Defective sperm function	[73]
	ML351	Inhibits ALOX-5	MIRI	[75]
	Docebenone	Inhibits ALOX-5/12 and lipid peroxidation	IS	[58]
	Troglitazone (TRO)	Inhibits ACSL4	-	[12]
	BRD4770	Downregulates LPO and MDA; upregulates SLC7A11, 4-HNE	Aortic dissection	[79]
	7- dehydrochole-sterol (7-DHC)	Inhibits lipid peroxide-tion	-	[80]
	Gossypol acetic acid (GAA)	Upregulates GPX4, downregulates ACSL4 and Nrf2	MIRI	[82]
Antioxidant	2-amino-5-chloro-N, 3-dimethylbenza-mide (CDDO)	Inhibits GPX4 degradation, lipid peroxidation and ROS	-	[83]
	Disulfiram (DSF), Fursultiamine	Disrupts GPX4 with HSC70; inhibits GPX4 degradation	-	[84]
	ADA-409–052	Inhibits lipid peroxidation	Embolic stroke	[85]
	Mitoglitazone (MGZ)	Upregulates GPX4; Inhibits lipid peroxidation	Renal I/R injury	[86]
	Sodium selenite	Upregulates GPX4	SCI	[87]
	PKUMDL-LC-101/LC101-D04	Upregulates GPX4	-	[58]
	Seratrodast	Activates system xₙ⁻/GSH/GPX4	Seizures	[88]
	Paeoniflorin (PF)	Downregulates Fe2+, ROS; upregulates SOD	AD	[89]
	Carvacrol (CAR)	Upregulates GPX4	IS	[90]
	Ginkgolide B (GB)	Regulates TFR1 and NOCA4; upregulates Nrf2/GPX4	AD	[91]
	Pachymic acid (PA)	Upregulates GSH, SLC7A11 and GPX4; Downregulates Fe2+, MDA, ROS	MIRI	[92]
	Kaempferol (KF)	Inhibits lipid peroxidation accumulation via Nrf2/SLC7A11/GPX4	IS	[93]
	Flavonoids (TFA)	Decreases ROS via SLC7A11/GPX4	Parkinson’s disease	[94]
	Galangin (Gal)	Decreases lipid peroxidation via SLC7A11/GPX4	Cerebral ischemia	[95]
	Alpha-lipoic acid (α-LA)	Increases xCT/GPX4	AKI	[96]
	Capsiate	Activates TRPV1/GPX4	Inestinal I/R injury	[97]
	San-Huang-Yi-Shen (SHYS)	Reduced iron overload via GSH/GPX4	Diabetic nephropathy	[98]
	Modified Shoutai Pill	Upregulates GPX4 and SLC7A11; decreases MDA and ACSL4	Recurrent pregnancy loss	[99]
	Angong Niuhuang Wan (AGNHW)	Activates PPARγ/AKT/GPX4	IS	[100]
	Uridine	Activates Nrf2/SLC7 A11/GPX4/HO-1	Sepsis-induced ALI	[101]
	Dithiolethiones (ACDT, D3T)	Activates Nrf2/xCT/GSH; reduced lipid peroxidation	Iron overload-induced cytotoxicity	[103]
	Propofol	Regulates SLC16A13/AMPK/GPX4	MIRI	[105]
	Metformin (Met)	Upregulates Nrf2, GPX4; decreases MDA	Vascular calcification	[107]
	Ajudecunoid C	Scavenges free radicals via activating Nrf2/AREs	Neurological diseases	[109]
	Dehydroabietic acid	Reduced ROS and lipid peroxidation; upregulates HO-1, GSH, GPX4 and FSP1 via Nrf2/ARE	Nonalcoholic fatty liver disease	[110]
	Proanthocyanidins (PACs)	Upregulates GSH, GPX4, SLC7A11 via Nrf2-HO-1	SCI	[110]
	Geraniin	Iron chelator; inhibits lipid peroxidation	-	[112]
	Quercetin (QCT)	Activates Nrf2/HO-1; uprgulates GPX4	IS	[113]
	Eriodictyol	Activates Nrf2/HO-1	AD	[38]
	Naringenin	Activates Nrf2/HO-1	Lung injury	[114]
	Tectorigenin	Suppresses Smad3; restores GPX4	Myocardial injury	[115]
	Biochanin A	Scavenges free radicals via Nrf2/System xc/GPX4	Knee osteoarthritis	[116]
	Isoliquiritin apioside	Downregulates Hif-1α and HO-1	Acute lung injury	[117]
	Puerarin	Upregulates Nrf2, SLC7A11, GPX4; inhibits COX-2	Retinal degradation	[118]
	Resveratrol	Activates Nrf2/GPX4	SCI	[119]
	Aloe-emodin	Activates Nrf2/SLC7A11/GPX4	Cardiac toxicity	[120]
	Withaferin A	Activates Nrf2/HO-1	Intracerebral hemorrhage	[121]
	Arbutin	Upregulates SLC7A11	Non-alcoholic fatty liver disease	[122]
	Dl-3-n-butylphthalide	Upregulates Nrf2 and GPX4	Parkinson’s disease	[123]
	Tetrahydroxy stilbene glycoside	Activates Keap1/Nrf2/ARE axis	AD	[124]
	β-caryophyllene	Decreased ROS and iron accumulation via Nrf2/HO-1	IS	[127]
	15,16-dihydrotanshinone I	Upregulates GSH/GSSG ratio, Nrf2/GPX4; reduced ROS	IS	[128]
	Dihydromyricetin	Upregulates GPX4; reduced Fe2⁺ and ACSL4	Cerebral I/R injury	[126]
	Forsythoside A	Activates Nrf2/GPX4; upregulates GSH	AD	[125]
	Rosiglitazone	Inhibits ACSL4; restores GPX4 and GSH	Renal I/R injury	[76]
	Pioglitazone	Inhibits ACSL4	-	[77]
	Compound 3f	Upregulates FSP1	IS	[129]
	Ginsenoside Rg1	Reverses xCT, GPX4 and FSP1; activates Nrf2	Neurodegenerative diseases	[130]
	Cardamonin	Regulates p53/SLC7A11/GPX4	Osteochondral injury	[131]

Inhibitors targeting iron metabolism

Iron chelators

Iron chelators attenuate Fenton chemistry by limiting redox-active iron and thereby restraining lipid peroxidation. Deferoxamine (DFO), an FDA-approved iron chelator, effectively inhibits ferroptosis by binding free Fe³⁺, decreasing ROS production, and upregulating ferroptosis-protective proteins such as GPX4, ferritin heavy chain 1 (FTH1), and system xₙ⁻ [30]. Clinical translation is constrained by DFO’s short half-life and poor oral bioavailability..

Oral chelators, including deferiprone (DFP) and deferasirox (DFX), were developed to overcome these limitations and showed improved pharmacokinetics [31, 32]. Their use is tempered by adverse effects such as granulocyte deficiency (DFP) and renal toxicity (DFX) [33, 34]. Next-generation agents aim to enhance efficacy and safety: CN128, which incorporates a glucuronidation “sacrificial” site, demonstrates superior oral activity and is under clinical evaluation for β-thalassemia [35]. DFA1, a deferric amine compound, exhibits potent chelation and ferroptosis suppression in vivo and in vitro [36].

Structure-guided optimization has yielded hybrid chelators with intrinsic radical-trapping capacity. Cinnamamide-hydroxypyridone derivatives bearing phenolic acid motifs increase both Fe-binding and ROS scavenging; among them, compound 9c surpasses DFP in preventing ferroptosis [31]. Dexrazoxane (DXZ), the only FDA-approved agent for preventing doxorubicin (DOX)-induced cardiotoxicity, exerts its protective effects by chelating mitochondrial iron and mitigating oxidative stress [37]. Membrane-permeable Fe²⁺ chelators such as 2,2′-bipyridine and phenanthroline reduce mitochondrial iron-dependent ROS and inhibit nanoparticle-induced ferroptosis in vitro [9].

Natural or repurposed chelators also show promise. M-30 shows the ability to permeate the blood–brain barrier and reduce amyloid precursor protein and Aβ levels, highlighting its potential application in Alzheimer’s disease (AD) [38]. Baicalein reverses the elastin-induced decrease in iron accumulation, GPX4, and GSH levels [39]. Hinokitiol chelates iron and activates Nrf2, suggesting a dual mechanism of suppression [40].

Tannins (TA) selectively binds free iron without interfering with endogenous iron-containing molecules [41]. BMS536924, a dual inhibitor of insulin-like growth factor (IGF) and insulin receptors, has been found to exert iron-chelating and ferroptosis-inhibitory effects [42]. Moreover, Thymosin β4, an endogenous iron chelator, plays a role in preventing ferroptosis by regulating intracellular free iron and ROS levels [43]. More recently, AKI-02, a hydroxypyridinone-based chelator, has shown promise in reducing iron overload-induced AKI and ferroptosis-related renal damage [44]. The FDA-approved antifungal drug ciclopirox functions as an iron chelator to evaluate the effect of ferroptosis stress in mild traumatic brain injury models [45] (Table 2).

Table 2.

Iron Chelators – Comparison of Efficiency, Oral Bioavailability, and Toxicity

Compound	Class	Reported Anti-ferroptosis Efficiency	Oral Bioavailability	Key Toxicities/Limitations	Advantages/Notes
Deferoxamine (DFO)	Classical chelator (hexadentate)	Moderate (benchmark)	Poor (IV/IM only)	Short half-life; injection-site reactions	Gold-standard Fe3⁺ chelator; robust anti-ferroptosis evidence
Deferiprone (DFP)	Bidentate chelator	Moderate–High	High (oral)	Agranulocytosis/neutropenia	Oral alternative to DFO; CNS penetration reported
Deferasirox (DFX)	Tridentate chelator	Moderate–High	High (oral)	Renal/hepatic toxicity; GI upset	Once-daily dosing; long half-life
CN128	Next-gen hydroxypyridinone	High (vs DFP)	High (oral)	Favorable in early reports	Sacrificial glucuronidation site; superior oral efficacy; clinical trials for β-thalassemia
DFA1	Deferric amine compound	High	Oral (reported)	Limited data	Enhanced chelation efficiency in vitro/in vivo
Compound 9c	Cinnamamide-hydroxypyridone derivative	Very high (≈10 × DFP)	Unknown/likely oral	Limited data	Dual chelation + radical scavenging
Dexrazoxane (DXZ)	EDTA analogue/pro-chelating agent	High (mitochondrial iron)	IV	Myelosuppression	Only FDA-approved for DOX cardiotoxicity prevention
Ciclopirox (CPX)	Hydroxypyridone antifungal	Moderate	High (oral/topical)	GI upset; off-label safety concerns	Repurposable; studied in brain injury models
AKI-02	Hydroxypyridinone chelator	High (AKI models)	Oral (preclinical)	Limited data	Reduces iron overload–induced AKI
M-30	Hydroxyquinoline chelator	Moderate	High (oral; BBB-permeable)	Limited data	Reduces APP/Aβ; potential neuro applications
Hinokitiol	α-Hydroxy ketone; ionophore-like	Moderate	High (oral)	Limited data	Chelation + Nrf2 activation; ↑SLC7A11/GPX4/HO-1
Tannins (TA)	Polyphenolic chelators	Moderate	Oral (dietary)	GI intolerance (high dose)	Selectively bind free iron; spare holo-proteins
2,2′-Bipyridine	Fe2⁺ chelator (research tool)	High (in vitro)	N/A	Not for clinical use	Reduces mitochondrial Fe-ROS; used as a lab reagent
Phenanthroline	Fe2⁺ chelator (research tool)	High (in vitro)	N/A	Not for clinical use	Often paired with bipyridine; blocks Fe-dependent ROS
Baicalein	Natural flavonoid (chelator + antioxidant)	Moderate	High (oral, natural)	Generally safe; GI upset at high doses	Chelates Fe; ↑GPX4/GSH; dual anti-ferroptosis activity
BMS536924	Dual IGF/insulin receptor inhibitor with chelation activity	Moderate	Oral (reported)	Limited safety data	Iron-chelating + ferroptosis-inhibitory effects

Non-iron chelators

Several small molecules attenuate ferroptosis by altering iron trafficking rather than directly chelating metal ions. YL-939 has been identified as a ferroptosis inhibitor through its interaction with 2PHB2, a protein involved in iron homeostasis. This interaction enhances ferritin expression and reduces intracellular iron levels, thereby providing protective effects against ferroptosis-induced liver injury [8]. Similarly, compound 9a, derived from benzimidazole scaffolds, stabilizes intracellular Fe²⁺ and improves neurological outcomes in the middle cerebral artery occlusion (MCAO) model of ischemic stroke (IS) [46].

NSC306711 blocks transferrin-transferrin receptor (Tf-TfR)-mediated uptake to limit iron influx [47]. DMT1 inhibitors, including pyrrolidine dithiocarbamate (PDTC) and benzylisothiourea, reduce NTBI levels, thereby slowing ferroptosis-related disease progression [48, 49].

Natural flavonoids have emerged as promising ferroptosis regulators. Carthamin yellow (CY) attenuates myocardial ischemia–reperfusion injury (MIRI) and reduces ROS accumulation in both in vivo and in vitro models [50]. Farrerol (FA) suppresses iron accumulation and lipid peroxidation, limiting ferroptosis-induced damage [51] (Fig. 2).

Fig. 2.

Ferroptosis inhibitors that target iron metabolic pathways. Ferric iron (Fe³⁺) is taken up by transferrin receptor 1 (TFR1) and internalized into endosomes, where it is reduced to Fe²⁺ by STEAP3 and transported into the cytosol via DMT1. Cytosolic Fe²⁺ forms the labile iron pool (LIP), which can be sequestered by chelators (e.g., DFP or DFX), stored in ferritin, or exported by ferroportin (FPN). Ferritinophagy, mediated by NCOA4, degrades ferritin to release Fe²⁺. Free Fe²⁺ catalyzes Fenton reactions, generating reactive oxygen species (ROS) that induce lipid peroxidation, leading to membrane damage and ferroptotic cell death. Ferroptosis inhibitors that activate the signaling are indicated by arrows. Ferroptosis inhibitors that inhibit the signaling are indicated by blunt arrows

Inhibition of ferroptosis via the lipid metabolism pathway

Endogenous free radical trapping antioxidants

Endogenous antioxidants neutralize lipid peroxyl radicals and reinforce cellular defenses. Vitamin E and its isoforms, particularly α-tocopherol (α-TOH), inhibit ferroptosis by reducing Fe³⁺ level and preventing lipid peroxidation [52]. Melatonin (MLT) exerts its ferroptosis-inhibitory effects by regulating ferritin levels, reducing lipid peroxidation, and activating the Nrf2/heme oxygenase-1 (HO-1) pathway, thereby providing neuroprotective effects in subarachnoid hemorrhage-related neuronal injury [53].

Vitamin K (VK) is a redox-active naphthoquinone that suppresses ferroptosis in GPX4-deficient mouse models [54]; menaquinone-4 (MK-4) acts as an electron donor to regenerate reduced antioxidants [55]. Additionally, recent findings suggest that vitamin K1 (VK1) may function as an effective endogenous antioxidant in mitigating AKI [54]. Trolox, a water-soluble vitamin E analog, reduces inflammatory cytokines and oxidative stress in early-stage non-alcoholic steatohepatitis (NASH) [56].

Exogenous free radical trapping antioxidants

Synthetic-free RTAs represent a major class of ferroptosis inhibitors. Ferrostatin-1 (Fer-1) stabilizes radicals and reduces ROS accumulation across various disease models [57]. Structure–activity relationship (SAR) studies have indicated that the N-cyclohexyl group serves as a critical lipophilic anchor for Fer-1’s activity [58]. SRS11-92, a Fer-1 analog, enhances metabolic stability but reduces plasma potency [59]. Further optimization yielded UAMC-2418 (improved stability but limited solubility) and UAMC-3203 (enhanced solubility, stability, and PK), which protects against organ damage without overt toxicity in mice [60].

Liproxstatin-1 (Lip-1), bearing a spiroquinoxaline amine scaffold, is efficacious in neurological disorders and cancers by inhibiting lipid peroxidation [61]. Lip-2 improves PK properties and prevents ferroptosis in lupus nephritis-derived human proximal tubular epithelial cells [62].

Phenothiazine derivatives also display RTA activity: compound 51 reduces elastin-induced ferroptosis and infarct volume in an MCAO model [57]; compound 7 J lowers DOX-induced cardiotoxicity with enhanced bioavailability and safety [63].

Clinically used agents with RTA properties include edaravone (EDA), which modulates GPX4/ACSL4/5-LOX and reduces neuroinflammation to promote recovery after spinal cord injury (SCI) [64], and Olanzapine (OLZ), which traps free radicals and suppresses RSL3-induced ferroptosis [65]; thiophene benzodiazepine derivatives, D:\WorkDIR\OPERATORS\QY31\2025\October\10-27\CAMLS_18_2025_5958_AMP-shared\Done exhibits 16-fold potency with minimal cytotoxicity [65].

Mitochondria-targeted RTAs-XJB-5–131 and JP4-039-suppress cytosolic ferroptosis in HT-1080 cells [66]; the refined compound (S)−6c, improves inhibitory activity approximately 30-fold vs JP4-039 [67]. Diacetylbis(N(4)-methylthiosemicarbazonato) copper(II) (CuATSM) reduces cerebral infarct size and oxidative stress in the transient MCAO model [68]. HW-3-based-4-hydroxy-pyrazoles yielded multiple inhibitors; compound 25 emerged as the most promising candidate [69].

Lipoxygenase (LOX) inhibitors

ALOX5 and ALOX15 catalyze PUFA peroxidation and promote ferroptosis [70]. ALOX5 inhibitors-zileuton, MK-886, BWA4C, and PD146176-exert anti-ferroptotic effects [71–73]. Zileuton reduces ROS and oxidative stress in retinal pigment epithelium (RPE) cells [74]. ML351, a specific ALOX15 inhibitor, limits erastin-induced cardiac ischemia–reperfusion injury [75]. Dual LOX inhibitors are also effective: docebenone (LOX-5/12 inhibitor) and baicalein (LOX-12/15 inhibitor) suppress lipid peroxidation [58].

ACSL4 inhibitors

ACSL4 promotes incorporation of PUFAs into phospholipids, sensitizing membranes to peroxidation and ferroptosis. Thiazolidinedione derivatives, including troglitazone (TRO), rosiglitazone, and pioglitazone (PIO), have been identified as effective ACSL4 inhibitors [12, 76, 77]. Notably, rosiglitazone enhances suppression of ferroptosis in GPX4-deficient mice [12]. Thrombin inhibitors have been reported to downregulate ACSL4 and ferroptosis [78].

Other inhibitors

Histone modulators can influence ferroptosis. The histone methyltransferase inhibitor BRD4770 lowers malondialdehyde (MDA) while increasing 4-HNE expression, reduces aortic lipid peroxidation, and improves cognitive function [79]. 7-dehydrocholesterol (7-DHC), prone to autooxidation, mitigates metabolic stress and acts as a ferroptosis inhibitor [80].

Abolane-type sesquiterpenoids (PBSs) from the deep-sea fungus Aspergillus floridus YPH1 include compound 7, which selectively blocks Erastin/RSL3-induced ferroptosis [81]. Gossypol acetic acid (GAA) decreases chelatable iron and lipid peroxidation in vitro and upregulates GPX4 expression in vivo, reinforcing its potential as a ferroptosis inhibitor [82].

Inhibition of ferroptosis via antioxidant action

The system Xc⁻–GSH–GPX4 axis

Reinforcement of the system Xc⁻–GSH–GPX4 axis remains a central anti-ferroptotic strategy. The triterpenoid compound 2-amino-5-chloro-N, 3-dimethylbenzamide (CDDO) inhibits heat shock protein 90 (HSP90), stabilizes GPX4, reduces lipid peroxidation, and limits ROS accumulation, thereby offering cellular protection [83]. Additionally, disulfide compounds such as disulfiram (DSF) and fursultiamine disrupt the GPX4-HSC70 interaction, inhibiting GPX4 degradation and enhancing ferroptosis resistance [84]. ADA-409–052 effectively suppresses tert-butyl hydroperoxide (TBHP)-induced lipid peroxidation and prevents ferroptosis triggered by GSH or GPX4 depletion. In a thrombotic mouse model, ADA-409–052 administration significantly reduced cerebral infarction, cerebral edema, and pro-inflammatory factor levels [85]. The antidiabetic drug mitoglitazone (MGZ) has also been found to enhance GPX4 expression while reducing lipid peroxidation, leading to significant renal protection in mice following I/R injury [86].

Se has been recognized as an essential regulator of ferroptosis through its ability to upregulate GPX4 and mitigate oxidative damage. In a rat model of SCI, sodium selenite administration significantly reduces iron, MDA, and 4-HNE levels while enhancing the FSP1/GPX4 pathway, ultimately improving motor function [87]. Recently, a metastable activation site on GPX4 has been identified, leading to the discovery of several GPX4 activators. Among them, PKUMDL-LC-101 and its analogue PKUMDL-LC101-D04 are the most effective in suppressing ferroptosis by increasing GPX4 enzymatic activity [58].

Additional small molecules and natural compounds have demonstrated ferroptosis-inhibitory potential through this pathway. Seratrodast, a thromboxane A2 receptor antagonist, significantly upregulates GPX4 levels and reduces lipid ROS, effectively preventing erastin-induced neuronal ferroptosis. In a mouse epilepsy model, seratrodast administration prolongs seizure latency and decreases seizure duration by enhancing GPX4 expression [88]. Similarly, paeoniflorin (PF), a monoterpene glycoside, improves cognitive function and reduces oxidative stress markers in brain tissue, thereby decreasing oxidative damage and alleviating neurological impairments in AD mice [89].

Carvacrol (CAR), a monoterpene phenol, effectively reduces lipid peroxidation markers and increases GPX4 expression, providing neuroprotection in IS models [90]. Ginkgolide B (GB), a terpene lactone derivative from Ginkgo biloba, modulates key ferroptosis markers, such as TFR1 and NOCA4, while enhancing Nrf2 and GPX4 expression, offering neuroprotective effects in AD mice [91]. Pachymic acid (PA), a lanolin-type triterpenoid, demonstrates ferroptosis-inhibitory properties by reducing MDA, ROS, and Fe²⁺ levels while upregulating GSH, SLC7A11, and GPX4, thereby alleviating MIRI [92].

Further studies have identified kaempferol (KF), a bioflavonoid, as a potent ferroptosis inhibitor. It enhances antioxidant defense mechanisms via the Nrf2/SLC7A11/GPX4 pathway, effectively preventing neuronal damage in oxygen–glucose deprivation/reperfusion (OGDR)-induced injury [93]. Additionally, total flavonoids from Aspergillus membranaceus (TFA) have shown neuroprotective effects in Parkinson’s disease (PD) models by increasing GSH levels and decreasing ROS accumulation [94]. Similarly, galangin (Gal) significantly reduces lipid peroxidation and enhances SLC7A11 and GPX4 expression in ischemia–reperfusion injury, ultimately protecting hippocampal neurons [95].

A-lipoic acid (LA), a mitochondrial cofactor, has been reported to enhance GSH and GPX4 expression while reducing ROS and lipid peroxidation. In folic acid-induced AKI models, LA effectively inhibited ferroptosis by reducing iron overload, mitigating ROS accumulation and lipid peroxidation, and increasing GSH and GPX4 levels [96]. Capsiate, a gut microbiota-derived metabolite, inhibits ferroptosis by activating the transient receptor potential vanilloid 1 (TRPV1) channel and upregulating GPX4 expression, thereby alleviating intestinal ischemia–reperfusion injury [97].

Traditional herbal medicines have also shown promise in ferroptosis inhibition. The San-Huang-Yi-Shen capsule (SHYS) significantly reduces Fe²⁺ levels while enhancing SLC7A11, GPX4, and GSH/GSSG levels, providing renal protection in diabetic nephropathy models [98]. Similarly, the Modified Shoutai Pill (Jianwei Shoutai Pill, JSP) upregulates GPX4 and GSH levels while decreasing MDA and ACSL4 protein expression, thereby mitigating lipid metabolism disorders in recurrent pregnancy loss models [99]. Another well-studied traditional formulation, Angong Niuhuang Wan (AGNHW), has demonstrated neuroprotective effects by modulating GPX4-dependent pathways and inhibiting ferroptosis [100] (Table 3).

Table 3.

Natural products and their ferroptosis-related targets

Compound/Natural Product	Clarified Target/Mechanism (ferroptosis-related)	Disease/Model (example)
Myricetin	Inhibits OGDR injury via Nrf2/SLC7A11/GPX4 axis	Neuroprotection (OGDR)
Shikonin	Modulates Nrf2/HO-1 and SLC7A11/GPX4; context-dependent ROS regulation	Multiple (model-dependent)
Kaempferol (KF)	Activates Nrf2 → ↑SLC7A11/GPX4; ↓lipid peroxidation	OGDR/neuronal models
Quercetin (QCT)	Activates Nrf2/HO-1; ↑GPX4; ↓ACSL4	Ischemic stroke
Resveratrol (RES)	Enhances Nrf2/GPX4 signaling; limits lipid ROS	Spinal cord injury (SCI)
Aloe-emodin (AE)	Activates Nrf2; ↑SLC7A11/GPX4; ↓oxidative stress	Cardiac toxicity
Arbutin (ARB)	Targets FTO/SLC7A11 axis; ↑SLC7A11	NAFLD
Paeoniflorin (PF)	Reduces oxidative stress; ↑GPX4, ↓ROS	Alzheimer’s disease models
Carvacrol (CAR)	↑GPX4; ↓lipid peroxidation	Ischemic models
Ginkgolide B (GB)	Regulates TFR1/NCOA4; activates Nrf2/GPX4	Alzheimer’s disease models
Pachymic acid (PA)	↑GSH/SLC7A11/GPX4; ↓Fe2⁺/ROS/MDA	Myocardial I/R injury (MIRI)
Capsiate	Activates TRPV1 → ↑GPX4	Intestinal I/R injury
Ginsenoside Rg1	Inhibits AIM2 inflammasome; activates Nrf2	Neuroinflammation
Cardamonin (CAD)	Modulates p53/SLC7A11/GPX4	Osteochondral injury
Galangin (Gal)	↓Lipid peroxidation via Nrf2/SLC7A11/GPX4 axis	Cerebral ischemia
TFA (Total flavonoids from A. membranaceus)	↑GSH, ↑GPX4; ↓ROS via Nrf2/SLC7A11 axis	Parkinson’s disease models
α-Lipoic acid (LA)	Enhances GSH/GPX4; ↓ROS and lipid peroxidation	Acute kidney injury (AKI)
SHYS (San-Huang-Yi-Shen capsule)	↓Fe2⁺; ↑SLC7A11, GPX4, GSH/GSSG ratio	Diabetic nephropathy
JSP (Modified Shoutai Pill)	↑GPX4, ↑GSH; ↓MDA, ↓ACSL4	Recurrent pregnancy loss
AGNHW (Angong Niuhuang Wan)	Activates PPARγ/AKT/GPX4; inhibits ferroptosis	Ischemic stroke

These findings highlight the intricate regulatory mechanisms of ferroptosis and underscore the therapeutic potential of targeting the System Xc⁻–GSH–GPX4 axis. Further research is needed to optimize these inhibitors and explore their clinical applications in ferroptosis-associated diseases.

Nrf2 pathway and ferroptosis inhibition

Uridine, a nucleoside composed of uracil and ribose, has demonstrated antioxidant, anti-inflammatory, and anti-aging properties [101]. Recent studies indicate that uridine suppresses macrophage ferroptosis by activating the Nrf2 signaling pathway, with the ferroptosis inhibitor Fer-1 further enhancing its protective effects [102]. Dithiolethiones, a class of lipophilic organosulfur compounds, including 5-amino-3-thioxo-3H-(1,2)dithiole-4-carboxylic acid ethyl ester (ACDT) and 3H-1,2-dithiole-3-thione (D3T), have been found to activate Nrf2 signaling pathway and increase cystine/glutamate antiporter system (System Xc⁻) and GSH levels in ferroptosis models [103, 104]. These compounds also elevate Nrf2-mediated ferritin and FPN expression, offering protection to glioblastoma cells against iron overload-induced cytotoxicity.

The anesthetic propofol has been shown to exhibit antioxidant properties by modulating the Nrf2/HO-1 pathway [105]. In a rat model of MIRI, propofol effectively mitigated ferroptosis by inhibiting SLC16A13 expression, activating the AMPK/GPX4 pathway, and protecting cardiac function [106]. Metformin (Met), a widely used first-line treatment for type 2 diabetes, attenuates oxidative stress by activating Nrf2/ARE pathway and promotes neural regeneration in SCI models [107]. Additionally, metformin upregulates GPX4 expression, activates Nrf2 signaling, reduces lipid peroxidation, and inhibits ferroptosis in vascular smooth muscle cells, thereby attenuating hyperlipidemia-induced vascular calcification [108]. Ajudecunoid C, a novel chlorane diterpenoid analogue, exhibits potent ferroptosis inhibition by activating the Nrf2-ARE pathway and scavenging free radicals [109]. Similarly, dehydroabietic acid, another diterpenoid, has been found to modulate the Keap1-Nrf2 axis and prevent non-alcoholic fatty liver disease [110].

Polyphenolic compounds have also been widely studied for their ability to regulate ferroptosis through the Nrf2 pathway. Proanthocyanidins (PACs) effectively scavenge free radicals and regulate lipoxygenase expression, increasing levels of GPX4, GSH, Nrf2, and HO-1, while downregulating ACSL4, thereby promoting functional recovery in SCI models [111]. The phenolic compound geraniin has been reported to inhibit ferroptosis in bmMSCs by suppressing lipid peroxidation, chelating Fe²⁺, and exhibiting strong antioxidant activity, without forming radical adducts [112]. Quercetin (QCT) activates the Nrf2-HO-1 signaling pathway, upregulates GPX4, downregulates ACSL4, and inhibits ferroptosis, thereby reducing neuronal damage and oxidative stress in cerebral IS [113].

Eriodictyol, a flavonoid, protects against ferroptosis-related neuronal damage in AD by activating Nrf2/HO-1 signaling pathway, reducing oxidative stress, and alleviating AD-like pathological changes [38]. Naringenin, a citrus-derived flavonoid, protects against silver nanoparticle-induced lung injury by reducing ferroptosis via the Nrf2/HO-1 signaling pathway [114]. Tectorigenin alleviates myocardial injury in sepsis by inhibiting ferroptosis through Smad3 suppression, restoring GPX4 expression, and mitigating oxidative stress and inflammation [115]. Biochanin A has also been identified as a potent ferroptosis inhibitor, suppressing iron accumulation and lipid peroxidation via Nrf2 signaling and mitigating osteoarthritis progression [116].

Isoliquiritin apioside, extracted from licorice, upregulates HIF-α and HO-1, thereby alleviating acute lung injury [117]. Puerarin mitigates ferroptosis by regulating iron-handling proteins, reducing lipid peroxidation via Nrf2 activation, and inhibiting COX-2, thereby protecting against iron overload-induced retinal degeneration [118]. The polyphenolic compound Resveratrol (RES) has been shown to promote ferroptosis-mediated recovery of motor function in SCI models by modulating Nrf2/GPX4 pathway [119]. Notably, both quercetin and resveratrol prevent iron-catalyzed hydroxyl radical formation, providing ferroptosis inhibition independent of Nrf2/ARE pathway. Aloe-emodin (AE), a natural anthraquinone derivative, activates Nrf2 and enhances SLC7A11 and GPX4 expression while reducing oxidative stress, thereby mitigating adriamycin-induced cardiotoxicity [120].

Several other compounds have been identified as Nrf2 pathway modulators with potential therapeutic applications. Withaferin A, a bioactive steroid ester, decreases oxidative stress and protects neuronal cells following intracerebral hemorrhage [121]. Arbutin (ARB), a natural phenolic glycoside, inhibits ferroptosis and alleviates non-alcoholic fatty liver disease by targeting the FTO/SLC7A11 axis, regulating gene methylation to enhance SLC7A11 expression [122]. Dl-3-n-butylphthalide (NBP), derived from celery extract, inhibits erastin-induced ROS accumulation and ferroptosis, offering protection against dopaminergic neuron loss [123]. Tetrahydroxy stilbene glycoside (TSG), an active component of Polygonum tigrinum, protects hippocampal neurons from ferroptosis-induced damage in AD by activating the Keap1/Nrf2/ARE axis [124]. Other small molecules, including β-caryophyllene (BCP), 15,16-dihydrotanshinone I (DHT), dihydromyricetin (DHM), and forsythoside A (FA), have demonstrated neuroprotective effects in neurological disorders by modulating Nrf2 signaling [125–128].

Other antioxidant pathways

Researchers have synthesized 14 analogs based on the structure of diphenylthiazole to enhance its inhibitory effects. Among them, compound 3f exhibits the highest biological activity, significantly alleviating neurological impairment in a rat model of MCAO following cerebral ischemia [129]. Similarly, ginsenoside Rg1, a bioactive ingredient derived from ginseng, has demonstrated protective effects against chronic neuroinflammation-induced neuronal ferroptosis by reducing oxidative stress, inhibiting the AIM2 inflammasome, and activating Nrf2 signaling pathway [130]. Cardamonin (CAD), a natural chalcone, has been reported to inhibit ferroptosis and prevent cartilage damage in rats by modulating the p53/SLC7A11/GPX4 signaling pathway [131] (Fig. 3).

Fig. 3.

Ferroptosis inhibitors that target antioxidant defense pathways. Ferroptosis is tightly regulated by multiple antioxidant systems that counteract phospholipid peroxidation. The primary cytosolic defense system is the SLC7A11–GSH–GPX4 axis: System Xc⁻ (composed of SLC7A11 and SLC3A2) imports cystine for glutathione (GSH) synthesis. GSH acts as a cofactor for GPX4, which detoxifies lipid hydroperoxides (PL-PUFA-OOH) into harmless lipid alcohols, thereby suppressing ferroptosis. Beyond this central pathway, complementary mechanisms provide backup protection: (1) The FSP1–CoQ₁₀ axis regenerates ubiquinol (CoQH₂) to neutralize lipid radicals at the plasma membrane; (2) In mitochondria, DHODH–CoQH₂ converts CoQ10 to CoQH₂, preventing mitochondrial lipid peroxidation; and (3) The GCH1–BH4 pathway generates tetrahydrobiopterin (BH4), a radical-trapping antioxidant that scavenges lipid peroxyl radicals and modulates CoQ synthesis. Additionally, oxidative stress triggers NRF2 release from KEAP1, activating antioxidant genes (e.g., SLC7A11, FSP1, HO-1) to prevent cellular oxidative damage. Ferroptosis inhibitors that activate the signaling are indicated by arrows. Ferroptosis inhibitors that inhibit the signaling are indicated by blunt arrows

Conclusions and perspectives

The interplay between lipid metabolism, iron homeostasis, and antioxidant defense mechanisms determines ferroptotic susceptibility, making it a highly regulated and therapeutically relevant process. Targeting ferroptosis offers opportunities to mitigate tissue damage in acute and chronic diseases while enhancing ferroptotic vulnerability in cancers resistant to conventional therapies [132, 133]. Importantly, ferroptosis plays a dual role in disease contexts: excessive activation contributes to ischemic stroke, neurodegeneration, and organ injury, whereas its induction provides tumor-suppressive benefits by eliminating metabolically stressed cancer cells.

Despite the remarkable progress, several challenges remain in ferroptosis research. The relative contributions of enzymatic versus non-enzymatic lipid peroxidation, as well as the precise role of mitochondria, continue to be debated. Beyond GPX4, emerging defense nodes such as FSP1–CoQ10 and DHODH–CoQH₂ operate in distinct cellular compartments and provide complementary protection, yet the extent of their compensatory activity when GPX4 is inhibited requires further clarification.

Clinical translation of ferroptosis modulators also faces significant bottlenecks, including bioavailability, limited tissue specificity, and potential toxicity or off-target [134, 135]. Tissue targeting is particularly challenging for neurological applications due to the blood–brain barrier, while optimization of CoQH₂ analogs exemplifies the need to improve metabolic stability. Innovative strategies such as nanocarrier-based delivery systems and prodrug design may help overcome these barriers. Moreover, integration of ferroptosis modulation with existing therapeutic regimens, coupled with a deeper understanding of its interplay with apoptosis, necroptosis, and autophagy, will likely broaden its clinical utility. Future directions should focus on optimizing pharmacokinetics and safety profiles, with strategies such as nanotechnology-based delivery systems and prodrugs offering promising solutions [142, 143]. Beyond mechanistic insights, the pharmacokinetic and pharmacodynamic properties of ferroptosis modulators present critical hurdles for clinical translation. Classical agents such as deferoxamine are hampered by poor oral bioavailability, limited tissue penetration, and off-target toxicities. Improving metabolic stability, tissue specificity, and dosing profiles will therefore be essential. Innovative approaches, including nanocarrier-based drug delivery platforms and prodrug strategies, are emerging as promising solutions to enhance the pharmacological performance of ferroptosis inhibitors and inducers, potentially bridging the gap between experimental efficacy and clinical application. Moreover, another critical challenge for clinical translation is the lack of standardized biomarkers to reliably monitor ferroptosis inhibition in patients. Current evaluations rely largely on indirect measures, including lipid peroxidation products such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), glutathione depletion, and alterations in iron metabolism. Emerging approaches, such as non-invasive iron imaging and the detection of oxidized phospholipid species, have shown promise but remain experimental. Establishing sensitive and disease-specific biomarkers will be essential to assess therapeutic efficacy, optimize patient selection, and guide the clinical application of ferroptosis modulators.

In conclusion, ferroptosis represents a powerful but double-edged sword in human disease. Addressing mechanistic uncertainties and translational barriers will be critical for harnessing its therapeutic potential and realizing effective interventions against some of the most challenging medical conditions (Table 4).

Table 4.

Abbreviation table

Abbreviation	Full Term
PUFA	Polyunsaturated fatty acid
PUFA-PL	Polyunsaturated fatty acid-containing phospholipid
PUFA-CoA	Polyunsaturated fatty acid acyl-CoA derivative
PUFA-OOH	Lipid peroxides derived from PUFA-PLs
GSH	Glutathione
GPX4	Glutathione peroxidase 4
GSSG	Glutathione disulfide
GR	Glutathione reductase
FSP1	Ferroptosis suppressor protein 1
CoQH₂	Ubiquinol (reduced form of Coenzyme Q10)
CoQ10	Coenzyme Q10 (ubiquinone)
GCH1	Guanosine triphosphate cyclohydrolase 1
BH4	Tetrahydrobiopterin
DHODH	Dihydroorotate dehydrogenase
NRF2	Nuclear factor erythroid 2-related factor 2
AKI	Acute kidney injury
AA	Arachidonic acid
AdA	Adrenic acid
ACSL4	Acyl-CoA synthetase long-chain family member 4
LPCAT3	Lysophosphatidylcholine acyltransferase 3
4-HNE	4-hydroxynonenal
4-HHE	4-hydroxyhexenal
LOX	Lipoxygenase
ROS	Reactive oxygen species
TFR1	Transferrin receptor 1
STEAP3	Six-transmembrane epithelial antigen of prostate 3 (metalloreductase)
DMT1	Divalent metal transporter 1
NTBI	Non-transferrin-bound iron
LIP	Labile iron pool
FPN	Ferroportin
ETC	Electron transport chain
SOD	Superoxide dismutase
TCA	Tricarboxylic acid cycle
AMPK	AMP-activated protein kinase
ACC	Acetyl-CoA carboxylase
AIFM2	Apoptosis-inducing factor mitochondria-associated 2
IMM	Inner mitochondrial membrane
DHO	Dihydroorotate
BH2	Dihydrobiopterin
DHFR	Dihydrofolate reductase
FDA	U.S. Food and Drug Administration
DFP	Deferiprone
DFX	Deferasirox
CN128	A novel hydroxypyridinone-based oral iron chelator
DFA1	Deferric amine compound
DXZ	Dexrazoxane
DOX	Doxorubicin
AD	Alzheimer’s disease
TA	Tannins
IGF	Insulin-like growth factor
Aβ	Amyloid-beta peptide
2PHB2	Prohibitin 2
AGNHW	Angong Niuhuang Wan
ALOX15	Arachidonate 15-lipoxygenase
ALOX5	Arachidonate 5-lipoxygenase
ALS	Amyotrophic lateral sclerosis
BCP	Beta-caryophyllene
CAD	Cardamonin
CuATSM	Diacetylbis(N(4)-methylthiosemicarbazonato) copper(II)
DHM	Dihydromyricetin
DHT	15,16-dihydrotanshinone I
FA	Farrerol
I/R	Ischemia/Reperfusion
IS	Ischemic stroke
JSP	Modified Shoutai Pill (Jianwei Shoutai Pill)
MCAO	Middle cerebral artery occlusion
MDA	Malondialdehyde
MGZ	Mitoglitazone
MIRI	Myocardial ischemia–reperfusion injury
MK-4	Menaquinone-4
NASH	Non-alcoholic steatohepatitis
NBP	Dl-3-n-butylphthalide
OLZ	Olanzapine
PDTC	Pyrrolidine dithiocarbamate
PIO	Pioglitazone
RPE	Retinal pigment epithelium
SAR	Structure–activity relationship
Se	Selenium
TBHP	Tert-butyl hydroperoxide
TRO	Troglitazone
TSG	Tetrahydroxy stilbene glycoside
Tf-TfR	Transferrin-Transferrin receptor
VK	Vitamin K
VK1	Vitamin K1
α-TOH	Alpha-tocopherol
SCI	Spinal cord injury
System Xc⁻	Cystine/Glutamate Antiporter System
AGNHW	Angong Niuhuang Wan
ACDT	5-amino-3-thioxo-3H-(1,2)dithiole-4-carboxylic acid ethyl ester
D3T	3H-1,2-dithiole-3-thione
Met	Metformin
PACs	Proanthocyanidins
QCT	Quercetin
RES	Resveratrol
AE	Aloe-emodin
ARB	Arbutin
NBP	Dl-3-n-butylphthalide
TSG	Tetrahydroxy stilbene glycoside
BCP	β-caryophyllene
DHT	15,16-dihydrotanshinone I
DHM	Dihydromyricetin
FA	Forsythoside A
CAD	Cardamonin
Lip-1	Liproxstatin-1
EDA	Edaravone
OLZ	Olanzapine
TRO	Troglitazone
PIO	Pioglitazone
7-DHC	7-dehydrocholesterol
GAA	Gossypol acetic acid
CDDO	2-amino-5-chloro-N,3-dimethylbenzamide
DSF	Disulfiram
MGZ	Mitoglitazone
PF	Paeoniflorin
CAR	Carvacrol
GB	Ginkgolide B
PA	Pachymic acid
KF	Kaempferol
TFA	Total flavonoids from Aspergillus membranaceus
Gal	Galangin
LA	α-Lipoic acid
TRPV1	Transient receptor potential vanilloid 1
SHYS	San-Huang-Yi-Shen capsule
JSP	Modified Shoutai Pill (Jianwei Shoutai Pill)

Author contributions

ZC had the idea for the review article; YH, KD, XF, XT, FW, YZ, JY, and YL performed the literature search; YH, KD and XF drafted the manuscript; ZC critically revised the manuscript.

Data availability

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Conflict of interest

The authors declare no conflict of interest.