Deferoxamine (DFO) has been approved by the Food and Drug Administration (FDA) for subcutaneous injection to mitigate elastin-induced ferroptosis in an in vitro ferroptosis model (Abdul et al., 2021). DFO inhibits ferroptosis by chelating free intracellular Fe³⁺, down-regulating ROS, and up-regulating intracellular levels of GPX4, the ferritin heavy chain (FTH1), and Cystine/glutamic acid reverse transporter (System Xc-) (Zhang et al., 2020; Zeng et al., 2021). Moreover, DFO has been shown to inhibit ferroptosis in SCI (Yao et al., 2019), but whether it directly protects neurons from ferroptosis is unclear. At the same time, DFO also plays a role in ischemic stroke (IS), which significantly reduces the area of cerebral infarction (Millán et al., 2021), and plays a certain neuroprotective role against the damage of neurological function after cerebral ischemia (Jones et al., 2022). However, a short DFO half-life was found during treatment. At the same time, two oral drugs, Deferiprone (DFP) and Deferasirox (DFX), have been developed to address the short half-life of DFO, but side effects such as granulocyte deficiency (Lecornec et al., 2022)and renal failure (Kattamis, 2019)are still present during treatment. To address the limitations of DFO, DFP, and DFX such as low oral activity, low efficacy, and side effects, Chen et al. introduced a sacrificial site for glucuronidation and designed and synthesized a novel oral iron chelator, CN128, and found that CN128 was more effective and efficacious orally (Chen et al., 2020), and it has been used in clinical trials in β-thalassemia patients after regular blood transfusions.

Deferric Amine Compounds DFA1 bind iron through two molecules of oxygen in the phenolic hydroxyl group and one molecule of nitrogen in the amine. Research has shown that DFA1 efficiently chelates iron in vivo and ex vivo, outperforming DFO. It has also been observed to alleviate iron overload-induced ferroptosis and reduce cytotoxicity in a mouse model of iron overload when administered orally and intravenously (Feng et al., 2022). Furthermore, DFA1 shows promise as a lead compound due to its high oral (Feng et al., 2022).

DFP was shown to have nephroprotective effects in a glycerol-induced AKI mouse model. Zhang et al. synthesized 25 novel iron chelator cinnamamide-hydroxypyridone derivatives by combining the iron chelating properties of DFP with the free radical scavenging capabilities of phenolic acids. Their assessment included assays for ABTS radical scavenging, Fe³⁺ affinity, oxygen radical absorbance capacity (ORAC), and the inhibition of Erastin-induced ferroptosis in HT22 cells. It was shown that compound 9c has both chelating iron ions and antioxidant properties. Compound 9c exhibited the strongest inhibition of ferroptosis, almost 10 times more potent than DFP (EC₅₀ = 14.89 μM). Additionally, the researchers observed that compound 9c significantly alleviated cisplatin (CP)-induced AKI in the HEK293T cell model (Rayatpour et al., 2022).

Dexrazoxane (DXZ) is the only drug approved by the FDA that can be used to prevent doxorubicin (DOX)-induced cardiotoxicity. DXZ has been reported to reverse DOX-induced ferroptosis mainly by chelating mitochondrial iron, and its co-administration with Ferrostatin-1 (Fer-1) increased survival in cardiomyopathic rats. Moreover, DOX upregulated GPX4 as well as FTH1 in H9c2 cells (Zhang et al., 2021; Huang et al., 2024). Meanwhile, studies have reported that 2,2′-Bipyridine exerts ferroptosis inhibition by chelating intra-mitochondrial iron (Chen et al., 2020). 1,10-Phenanthroline resembles and downregulates mitochondrial ROS accumulation and inhibits ferroptosis induced by zero-valent iron nanoparticles in vitro with 2,2′-Bipyridine (Huang et al., 2019; Chen et al., 2020). Furthermore, the N, N-dimethylaniline structure of the novel iron chelator GIF-2197-r is crucial for ferrous ion coordination and ferritin resistance (Hirata et al., 2023). In addition, Yael Avramovich-Tirosh et al. reported that the synthetic iron chelator [5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline] (M-30), which permeates the BBB and reduces cellular APP and Aβ production levels, was shown to alleviate the intellectual disability in mice after AD in an in vivo animal model (Avramovich-Tirosh et al., 2007; Zhang et al., 2022).

In addition, studies have shown that natural compounds also can chelate iron. The flavonoid baicalein significantly reverses elastin-induced downregulation of iron accumulation, GSH, and GPX4 in cells (Xie et al., 2016). Experimental screening yielded Hinokitiol, a natural molecule carrying an α-hydroxy ketone skeleton with strong iron chelating properties, which can activate nuclear factor red factor 2-related factor 2 (Nrf2), providing a basis for further neuroprotection (Sridharan and Sivaramakrishnan, 2018). Tannins (TA), which complex with iron without binding to endogenous iron-containing molecules, are also an effective measure for the treatment of diseases associated with iron overload (Phiwchai et al., 2018). BMS536924 a dual inhibitor of insulin-like growth and insulin receptor protects against the induction of iron-dead cells and can act as an iron chelator to block ferroptosis (Kuganesan et al., 2021). Thymus β4 is an endogenous iron chelator that regulates ferroptosis by affecting free iron ions and ROS (Lachowicz et al., 2022). Ciclopirox (CPX) (Eberhard et al., 2009; Lin J. et al., 2021; Lu et al., 2022) has been approved by the FDA for antifungal therapy, and in recent years it has been found that intraperitoneal injection can significantly inhibit the growth of non-small cell lung cancer (NSCLC). Therefore, the use of iron chelation therapy in clinical practice still holds great promise.

In addition to iron chelators, several compounds have been found to inhibit ferroptosis by modulating iron metabolism and are used in disease treatment.

Yang et al. screened a non-classical inhibitor of ferroptosis, YL-939, from chemical libraries. They found that YL-939 binds to its target inhibitor 2PHB2 and promotes ferritin expression to reduce iron levels to inhibit ferroptosis and alleviate ferroptosis-mediated liver injury (Yang et al., 2022). Compound YL-939 provides a new intervention strategy for diseases associated with ferroptosis.

Phenotypic screening and structural modification identification of benzimidazole derivatives and discovery of a novel ferroptosis inhibitor compound 9a by Fang et al. They found that compound 9a inhibited ferroptosis mainly by stabilizing intracellular Fe²⁺. In the middle cerebral artery occlusion (MCAO) model, compound 9a was found to significantly alleviate neurological impairment after IS. In addition, compound 9a can bind to NCOA4 and break the NCOA4-FTH1 interaction (Fang et al., 2021).

A National Cancer Institute screen found that the polycyclic aromatic compound NSC306711 blocked iron uptake by the Tf-TfR pathway and inhibited ferroptosis. At the same, unlike classical lattice protein-mediated endocytosis of Tf receptors, this drug is also known as ferritin due to its different previous endocytosis pathway that induces internalization and degradation of unoccupied Tf receptors (Horonchik and Wessling-Resnick, 2008).

Study demonstrates that DMT1 inhibitors reduce DMT1-mediated non-transferrin bound iron (NTBI) and play a role in ferroptosis-mediated disease (Sun et al., 2023). These include inhibitors such as pyrrolidine dithiobarbamate (PDTC) (Wetli et al., 2006) and benzylisothiourea (Zhang et al., 2012).

The complex Chinese herb Naotai formula extract (NTE) has been reported to modulate FPN-1, downregulate TFR1 and DMT1 levels, and reduce ROS and MDA accumulation (Yang T. et al., 2021). NTE was found to upregulate rat Recombinant Solute Carrier Family 7, Member 11 (SLC7A11), GPX4, and GSH levels in the MCAO model (Lan et al., 2020; Qiu et al., 2022). Meanwhile, the flavonoid compound Carthamin yellow (CY) has been shown in ex vivo and in vivo experiments to be useful in myocardial ischemia-reperfusion (MIRI) injury and to reduce ROS. In recent years, Guo et al. found downregulation of Fe²⁺, ROS, reverse transcription of Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4), Fe²⁺, TFR1, Glutathione (GSH), SOD, and MDA levels in the brain and improvement of infarct size in the rat brain after administration of the drug in MCAO models (Guo et al., 2021; Chen G. et al., 2022). In addition, the natural flavonoid Farrerol (FA) may alleviate ferroptosis by inhibiting iron accumulation and lipid peroxidation (Wu et al., 2022).

Free radical trapping antioxidants (RTAs) inhibit ferroptosis and protect hydrocarbon systems by trapping lipid peroxyl radicals. Fer-1 and Liproxstatin-1 (Lip-1) (Zilka et al., 2017), both obtained by high-throughput screening of small molecule libraries, rapidly transfer H atoms from their arylamine portions to lipid radicals to inhibit lipid peroxidation and prevent free radical chain reactions in membrane PUFA lipids (Bayır et al., 2020; Scarpellini et al., 2023). Current researchers have identified quite a few other exogenous RTAs and many endogenous RTAs that play a role in iron-death-mediated diseases (e.g., Table 1).

Lipoxygenase (LOX) is thought to be a central player in ferroptosis. It induces lipid peroxidation by reacting with ROS and catalysing PUFA, which in turn induces ferroptosis. It has been found that humans have six LOX isoforms, ALOX5, ALOX12, ALOX12B, ALOX15, ALOX15B, and ALOXE3, and there are already some cells that can be rescued by LOX inhibitors. LOX inhibitors inhibit LOX primarily by trapping free radicals (Shah et al., 2018a), which in turn inhibits lipid peroxidation. The most relevant inhibitors reported in the article are LOX-5 inhibitors, including zileuton (Liu et al., 2015; Lee et al., 2022), MK-886 (Shi et al., 2023), BWA4C (Franchi-Miller and Saffar, 1995), PD146176 (Walters et al., 2018) and others. Furthermore, it was found that the LOX-5 inhibitor Zileuton is involved in oxidative stress in retinal pigment epithelium (RPE) cells and regulates retinal ROS. It provides an effective solution for the treatment of retinal diseases (Liu et al., 2015; Lee et al., 2022). LOX-5 expressed during inflammation uptakes apoptotic cells, activates resident macrophage populations, and thus maintains apoptotic cell tolerance (Kapralov et al., 2020). Also, ML351 specifically inhibits ALOX-15 and alleviates erastin-induced cardiac ischemia/reperfusion (I/R) injury (Cai et al., 2023; Horinouchi et al., 2024). In addition, the LOX-5/12 inhibitor docebenone (AA-861), and the LOX-12/15 inhibitor baicalein have all been found to inhibit lipid peroxidation (Scarpellini et al., 2023) and play a role in ferroptosis-mediated diseases.

The insulin sensitising drugs thiazolidinediones (TZD) are a class of peroxisome proliferator activatedreceptor γ (PPARγ) activators. Troglitazone (TRO), rosiglitazone (ROSI) and pioglitazone (PIO) were found to effectively and specifically inhibit ACSL4 (Kim et al., 2001), and TRO being TZD-protective due to its 6-chromophoranol structure (Doll et al., 2017). Pharmacological evaluation of ACSL4 revealed that GPX4KO mice treated with ROSI showed better inhibition of ferroptosis (Doll et al., 2017). In addition, thrombin inhibitors also inhibit ACLS4 and ferroptosis (Zhang et al., 2024a).

Histone methyltransferase inhibitors (BRD4770) is comparable to Fer-1 inhibition at optimal concentrations (Chen et al., 2022b; Chen et al., 2022c) and may be useful in the treatment of stenosis. The researchers screened and found that BRD4770 exhibited significant ferroptosis inhibition. They further found that BRD4770 inhibited lipid peroxidation by down-regulating PLO and MDA levels and increasing 4-HNE expression. And BRD4770 upregulated the mRNA levels of ferroptosis regulators SLC7A11, Recombinant Solute Carrier Family 3, Member 2 (SLC3A2), GPX4, and FSP1. Furthermore, it was found that BRD4770 alleviated cognitive impairment and downregulated aortic lipid peroxidation in a mouse model of AD (Chen et al., 2022b). Thus, BRD4770 is expected to be an effective molecular drug for the treatment of AD.

Recently Florencio Porto Freitas et al. identified 7-dehydrocholesterol (7-DHC), an endogenous ferroptosis inhibitor, as one of the lipid components susceptible to autotrophication in vivo. They prepared soybean phosphatidylcholine (PC) monolayers loaded with 7-DHC and found that 7-DHC is preferentially oxidised in vitro and that the oxidation of 7-DHC in vitro is critical for the inhibition of (phospho)lipid peroxidation. Subsequently, using the iron/ascorbate couple as a model for oxidative sources, they found that 7-DHC accumulation protects (phosphoric acid) lipids from autoxidation and subsequent rupture and is different from previous lipid peroxidation, mainly due to its better reactivity to peroxyl radicals. In addition, 7-DHC accumulation significantly reduces metabolic stress in the body (Angeli et al., 2021; Freitas et al., 2024). Thus, 7-DHC regulates ferroptosis in an easily overlooked manner by inhibiting lipid peroxidation and bringing new therapeutic ideas to ferroptosis-mediated diseases.

In recent years, researchers have isolated seven abolane-type sesquiterpenoids (PBSs) from the deep sea fungus Aspergillus floridus YPH1 (Li et al., 2023b), with compound 7 showing a selective inhibitory effect on Erastin/RSL3-induced ferroptosis similar to Fer-1. However, unlike Fer-1, compound 7 exhibited negligible radical scavenging activity in 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays (Li et al., 2023b). Additionally, PBSs25 gossypol acetic acid (GAA) was found to protect cardiomyocytes from ferroptosis in vitro by reducing chelated iron and lipid peroxidation. In vivo studies showed that GAA significantly upregulated GPX4 (Lin et al., 2021).

The heat shock protein 90 (HSP90) plays an important role in protein maturation, stabilisation, and activation (Wickramaratne et al., 2023). A triterpenoid compound 2-amino-5-chloro-N, 3-dimethylbenzamide (CDDO) was identified by Wu et al. It inhibits HSP90, which in turn inhibits GPX4 degradation and lipid peroxidation, and downregulates ROS, protecting cells from damage caused byferroptosis (Wu et al., 2019). Furthermore, in 2022 Liu et al. found that a series of disulfide compounds, such as disulfiram (DSF) and fursultiamine, could disrupt the interaction of GPX4 with HSC70, which in turn inhibited GPX4 degradation and protected cells from ferroptosis (Liu et al., 2022).

In 2021 Meike Hedwig Keuters et al. found that the novel ferroptosis inhibitor arylthiazyne derivative small molecule (ADA-409-052) inhibited tert-butyl hydroperoxide (TBHP)-induced lipid peroxidation and prevented ferroptosis induced by GSH, as well as GPX4 deficiency. It is rapidly absorbed after oral administration in a mouse model. In addition, administration of the drug in a thrombotic mouse model revealed a significant decrease in the area of cerebral edema, the area of cerebral infarction, and the expression of pro-inflammatory factors in mice (Keuters et al., 2021). Thus, small molecule inhibitors such as ADA-409-052 offer new therapeutic strategies for neurological disorders as well as acute brain injury.

In 2023, Qi et al., 2023 reported that the antidiabetic drug mitoglitazone (MGZ) upregulated GPX4 and reduced lipid peroxidation, thereby significantly alleviating renal injury in mice after I/R, providing a new therapeutic strategy to ameliorate renal I/R injury. In addition, MGZ can also exert a nephroprotective effect by maintaining the normal morphology of mitochondria.

The catecholamine neurotransmitter Dopamine (DA) plays a role in human cognitive functions. It was shown that DA enhances the stability of GPX4 protein (Costa and Schoenbaum, 2022). Increased survival of DA ergic neurons and reversal of ROS, GPX4, and FTH1 levels in SNpc after moxibustion application in a Parkinson’s disease (PD) model and improvement of motor deficits in it. And DA agonists reduce the risk of side effects during recovery (Ding et al., 2023). In addition, levodopa is approved for use in patients with early or late stroke and can be used in combination with physiotherapy (Obi et al., 2018). DA-mediated ferroptosis has been mentioned in other diseases and is expected to lead to new research directions in ferroptosis-mediated diseases.

The study reports that Se inhibits ferroptosis and protects neurons by enhancing GPX4 expression. Se acts in the antioxidant pathway mainly by containing selenoproteins (Ramakrishnan et al., 2022; Choi et al., 2023). The study reports that Se inhibits ferroptosis and protects neurons by enhancing GPX4 expression (Alim et al., 2019). Inadequate levels of organismal Se downregulate GPX4 and antioxidant enzymes and upregulate ROS, MDA, and LPO (Xu et al., 2023). Se alleviates cerebral ischemia-induced neurological damage by activating GPX4 in IS (Alim et al., 2019). Iron, MDA and 4-HNE were found to be downregulated and promote the FSP1/GPX4 pathway after sodium selenite injection in a rat model of SCI, which in turn improved motor function in rats (Chen et al., 2022). In addition, injection of double selenium nanospheres (CLNDSe) in an AD mouse model revealed abnormal microglia protofibrils or tau protein-targeted aggregation outside of Aβ42, and its crossing of the BBB into the brain significantly downregulated ROS, ACSL4, and COX-2, and upregulated FTH1, GPX1, and GPX4, ultimately inhibiting ferroptosis and ameliorating cognitive deficits in APP/PS1 mice (Solovyev et al., 2018). Overall, the trace element Se has been found to play a role in a variety of diseases by mediating ferroptosis.

Recently Li et al., 2019 identified a potent GPX4 metastable site and obtained eight GPX4 metastable activators by structural analysis and computational design (Scarpellini et al., 2023). They inhibit ferroptosis by activating GPX4 enzyme activity (IC₅₀ > 100 μM). Compound PKUMDL-LC-101 and its analogue PKUMDL-LC-101-D04 most efficiently activated and increased GPX4 activity in intact cells while inhibiting ferroptosis in a cellular model (Scarpellini et al., 2023). These compounds provide an effective strategy for the future development of activators for other protein targets and also lead to new therapeutic strategies for lipid peroxidation-related diseases such as neurodegenerative diseases (Li et al., 2018; Li et al., 2019).

Upregulation of GPX4 levels and downregulation of lipid ROS in neurons after treatment with the thromboxane A2 receptor antagonist Seratrodast and consequent inhibition of neuronal cell ferroptosis in erastin-induced hippocampal HT22 cells. And Seratrodast increased GPX4 expression and shortened seizure duration and prolonged seizure latency in a mouse model of epilepsy (Noack et al., 2017). Thus Seratrodast could play a role in several diseases by inhibiting ferroptosis.

Using APP/PS1 mice as subjects, researchers found that the monoterpene glycoside paeoniflorin (PF) improved cognitive performance and downregulated the levels of Fe²⁺, MAD, and ROS in brain tissue, which reduced oxidative damage and thus alleviated the neurological damage in AD mice (Zhang and Wei, 2020; Zhai et al., 2023). And PF can reverse AKI by inhibiting SLC7A11-mediated ferroptosis (Ma et al., 2023). In 2019, Guan et al. found that the monoterpene oenol carvacrol (CAR) (Abdul Ghani et al., 2023) reduced PLO levels in ischemic gerbil brain tissue and inhibited ferroptosis by up-regulating GPX4, which exerted neuroprotective effects in both in vivo and ex vivo models of IS. Thus, CAR has the potential to be an effective therapeutic agent for IS. In 2021, Li et al. found that injection of Ginkgolide B (GB), the active ingredient of terpene lactones (Wang et al., 2020), in an animal model of AD reversed the levels of TFR1 and NOCA4 and upregulated the expression of Nrf2 and GPX4 in the brains of SAMP8 mice, which exhibited neuroprotective effects in AD mice (Hébert et al., 2022).

The lanolin-type triterpenoid Pachymic Acid (PA) has a variety of pharmacological properties. Liu et al. established a cellular myocardial infarction (MI) model after administration of 20 μg/mL and found that the inhibitory effect of oxygen-glucose deprivation/reperfusion (OGD/R) on cell viability was reversed and the levels of MDA, ROS, and Fe²⁺ were downregulated, and the expression of GSH, SLC7A11, and GPX4 was increased. Meanwhile, PA inhibits cardiomyocyte ferroptosis in a dose-dependent manner and attenuates MIRI injury in mice (Liu et al., 2024).

Flavonoids are an important class of phenolic metabolites in plants with good antioxidant effects. The bioflavonoid Kaempferol (KF) has shown neuroprotective effects in neurological disorders such as IS and AD. Recently, it was found that KF activated the Nrf2/SLC7A11/GPX4 signalling pathway and enhanced antioxidant capacity, which in turn reversed OGDR-induced ferroptosis (Holland et al., 2020; Kim et al., 2023) and alleviated neuronal cell damage. The natural flavonoid compound Icaritin (ICA) plays a role in a variety of diseases such as IS, AD, depression, and others. It directly binds to Nrf2 and promotes GPX4 transcription, which in turn inhibits ferroptosis after IRI and ameliorates brain damage (Choi et al., 2023). In recent years, ICA compounds significantly enhanced GSH-Ps, SOD activities and alleviated oxidative stress injury in mouse brain tissue after gastric administration of ICA compounds in APP/PS1 double transgenic mice. In addition, ICA was found to alleviate cognitive deficits in AD mice in a dose-dependent manner in the Morris water maze (VWM) (Angeloni et al., 2019; Zheng et al., 2023).

Total flavonoids from Aspergillus membranaceus (TFA) play a role in neurodegenerative diseases. Gao et al., 2024 found that TFA prevented SH-SY5Y cell neurotoxicity by increasing GSH and GSH/GSSG ratios and decreasing ROS, and showed significant neuroprotection in MPTP/MPP-induced in vitro and in vivo PD mouse models. Simultaneous injection of the flavonoid galangin (Gal) after I/R injury in VWM revealed a significant reduction in lipid peroxidation levels and an upregulation of SLC7A11 and GPX4 expression in the gerbil brain, which resulted in the inhibition of ferroptosis and the protection of hippocampal neurons in the gerbil brain after I/R (Guan et al., 2021; Hassanein et al., 2023). At the same time, gerbils showed significant improvement in the area of learning memory. Recently, Yang et al. found that Gal prevented iron overload and lipid peroxidation in a MIRI model and significantly attenuated myocardial fiber damage, reduced cerebral infarct size, and improved cardiac function by targeting the GPX4/Nrf2 signalling pathway in mice after MIRI (Salama and Elshafey, 2021). Thus flavonoids are a promising inhibitor of ferroptosis.

Α-lipoic acid (LA) reverses folic acid (FA)-induced AKI. In 2021, Xue et al. found that LA upregulated GSH, GPX4, and downregulated ROS as well as lipid peroxidation, and that supplementation with LA reversed the low expression of SLC7A11 (Li et al., 2021). In addition, LA also inhibits ferroptosis and attenuates fluoride-induced liver injury by modulating the Xc-GSH-GPX4 axis and chelating iron (Cho et al., 2022).

In addition to the above-mentioned small molecule drugs, many herbal medicines have also been found to play a role in herbal medicines have also been found to play a role in ferroptosis-mediated diseases. For example, Lv et al. established a diabetic nephropathy (DN) mouse model and found that Fe²⁺ was downregulated and SLC7A11, GPX4 content, and GSH/GSSG content, and GSH/GSSG were upregulated in the renal tissues of mice after San-Huang-Yi-Shen capsule (SHYS) administration and that it alleviated renal injury (Su et al., 2021; Lv et al., 2023). At the same time, Modified Shoutai Pill, also known as Jianwei Shoutai Pill (JSP), upregulated GSH, GPX4, downregulated MDA levels, and ACSL4 protein expression in the placenta of Recurrent Pregnancy Loss (RPL) mice, and was shown to protect against RSL3-induced lipid metabolism (Zhang et al., 2023; Lai et al., 2024). Futhermore, Angong Niuhuang Wan (AGNHW) has recently been found to exert neuroprotective effects by modulating GPX4-related signaling pathways and inhibiting ferroptosis (Bai et al., 2024).

Uridine, composed of uracil and ribose, exhibits anti-inflammatory (Jeengar et al., 2017), antioxidant (Adant et al., 2022), and anti-aging (Krylova et al., 2021) properties. Kai Lai et al. (2023) discovered an increase in uridine phosphorylase 1 (UPP1) in an ALI model induced by lipopolysaccharide (LPS), leading to elevated uridine levels and the upregulation of SLC7A11, GPX4, and HO-1 expression. Moreover, Uridine was found to inhibit macrophage ferroptosis by activating the Nrf2 signaling pathway, with the protective effect enhanced by Fer-1. Therefore, supplementing with Uridine may offer potential therapeutic benefits for ALI (Lai et al., 2023).

Dithiolethiones, lipophilic organosulfur compounds (Ansari et al., 2018), such as 3H-1,2-dithiole-3-thione (D3T) and 5-amino-3-thioxo-3H-(1,2)dithiole -4-carboxylic acid ethyl ester (ACDT), activate Nrf2 and increase system Xc- and GSH levels in the erastin-induced ferroptosis model, demonstrating antioxidant effects and significant inhibition of ferroptosis akin to Fer-1 (Kulkarni et al., 2023). Treatment with D3T and ACDT upregulated Nrf2-mediated expression of ferritin and FPN1, while also protecting U-87MG cells from iron overload-induced cytotoxicity (Kulkarni et al., 2023). Additionally, D3T upregulates silent information regulator 1 (SIRT1), Nrf2, and HO-1, ameliorating cognitive deficits in the Tg2576 AD mouse model (Cui et al., 2018). Notably, D3T exhibits neuroprotective effects in neuroinflammation and IS, suggesting its potential as a treatment option for ferroptosis-related diseases.

In 2022, Fan et al., 2023 discovered that the anaesthetic Propofol (Islam et al., 2020) could have a strong antioxidant effect by modulating Nrf2/GPX4 through protein blotting, transmission electron microscopy, and glutathione assays. Furthermore, in a mouse model of CIRI, Propofol was shown to effectively prevent ferroptosis and protect against neuronal damage in the brain after cerebral ischemia/reperfusion.

Metformin (Met), a biguanide derivative commonly used in the first-line treatment of type 2 diabetes, has also shown promise in various other conditions such as cancer, cardiovascular disease, and neurological disorders (Ala and Ala, 2021). Recent research has unveiled Met’s potential role in spinal cord injury (SCI) by inhibiting oxidative stress through the Nrf2/ARE pathway (Wang et al., 2020) and promoting neural regeneration post-SCI, offering new therapeutic possibilities. Additionally, studies have indicated that Met upregulates GPX4 (Ma et al., 2021), reduces MDA levels, and provides protection against neurological impairments following cerebral ischemia (Cai Z. et al., 2023).

The novel chlorane diterpenoid analogue Ajudecunoid C (ADC) is more effective in ferroptosis inhibition. It has been shown that ADC mainly acts on the Nrf2-AREs pathway and scavenges free radicals to exert an ferroptosis inhibitory effect, and ADC may interfere with the Keap1-Nrf2 pathway and activate the Nrf2-AREs pathway (Tan et al., 2021). In addition, the diterpenoid Dehydroabietic Acid activates the Keap1/Nrf2-ARE signalling pathway and attenuates non-alcoholic fatty liver disease (NAFLD). Therefore, researchers have proposed that diterpenoids may be effective compounds for inhibiting ferroptosis (Tan et al., 2021).

Biopolyphenolics Proanthocyanidins (PACs) are effective free radical scavengers. PACs have been reported to also have the ability to regulate LOX (Zhou et al., 2020). PACs have been found to inhibit ferroptosis and play a role in a variety of diseases by altering the expression of iron-related factors. For example, PACs upregulate the expression of GSH, GPX4, SLC7A11, Nrf2, and HO-1 and downregulate the expression of TFR1, ACSL4 and regulate SCI, thereby promoting ferroptosis-mediated functional recovery in SCI mice (Zhou et al., 2020). In addition, a large number of studies have shown that PACs activate the Nrf2-HO-1 pathway and ameliorate CIRI, bringing a new direction for CIRI treatment (Chumboatong et al., 2020). In 2022, Yuan et al. found downregulation of oxidative stress and neuronal death after injection of the phenolic substance geraniin by the middle cerebral artery occlusion-reperfusion (MCAO/R), and OGD/R models, as well as by neurological scoring assays, CCK8 assessment, TUNEL staining, detection of cells by flow cytometry, and Western blotting assessment (Chen et al., 2021). Meanwhile, they found that the infarcted portion of brain tissue upregulated ex vivo and in vivo Nrf2, HO-1 protein expression in a concentration-dependent manner in the tMCAO model (Chumboatong et al., 2020). Thus, the neuroprotective effect of geraniin may be closely related to the Nrf2/HO-1 signalling pathway, but further experimental elucidation is needed in the future.

Flavonoids have been implicated in ferroptosis-related diseases through their interaction with Nrf2. For example, quercetin (QCT), a natural flavonoid, has been shown to alleviate renal injury by activating the Nrf2-HO-1 signaling pathway (Kato et al., 2023). Studies using an AKI-I/R model demonstrated that QCT administration led to increased cell viability, upregulation of ALC7A11, SLC3A2, and GSH expression, as well as a reduction in MDA and lipid ROS content in mice (Cruz-Gregorio and Aranda-Rivera, 2023). QCT also shows promise in the treatment of neurological disorders such as Parkinson’s disease (PD) (Jiang et al., 2023). Eriodictyol, another flavonoid, was found to upregulate Nrf2/HO-1 and reduce ROS levels in a renal injury model, providing protection against CP-induced AKI (Badi et al., 2024). Furthermore, Eriodictyol has been shown to inhibit ferroptosis and improve cognitive deficits in APP/PS1 mice through activation of the Nrf2/HO-1 pathway (Li et al., 2022; Zhang et al., 2022). Naringenin, a flavonoid derivative from citrus extract, has demonstrated efficacy in alleviating myocardial injury by modulating the Nrf2/system Xc-/GPX4 axis (Shamsi et al., 2021). It also shows potential in mitigating ferroptosis induced by silver nanoparticles in human bronchial epithelial BEAS-2B cells through the Nrf2/HO-1 axis (Zhang et al., 2022b). Hesperidin and naringin have both been found to inhibit ferroptosis by upregulating the Nrf2 pathway, offering protection to human myeloid cells (Tang et al., 2022; Zhu et al., 2023).

The isoflavone tectorigenin protects against unilateral ureteral obstruction and renal injury in rats by affecting NADPH oxidase 4 (NOX4) expression (Li et al., 2022). Biochanin A, an active isoflavone of Astragalus membranaceus, inhibits ferroptosis by modulating the Nrf2/system Xc-/GPX4 signalling pathway, decreasing TFR1 and ferritin levels, and relieves knee osteoarthritis (KOA) (He et al., 2023). Licorice extract chalcone isoiquiritin apioside inhibits ferroptosis mediated ALI through upregulation of HIF-α and HO-1 proteins (Zhongyin et al., 2022). Puerarin, a natural isoflavone extracted from Pueraria Mirifica, was found to be protective against neuronal cell damage in mice by modulating Nrf2 in the OGD/R model (Li and Liu, 2024). It was also demonstrated to downregulate Fe²⁺, cyclooxygenase 2 (COX2), and upregulate Nrf2 and its downstream related ferritin (including SLC7A11, GPX4, HO-1) expression to reduce lipid peroxidation and inhibit retinal ferroptosis (Song et al., 2024). In addition, Puerarin was found to downregulate p53 and effectively improve neurological impairments in patients with ischemic brain injury in combination with conventional treatment in the clinic (Hou et al., 2024).

The non-flavonoid polyphenolic compound Resveratrol (RES) was found to promote ferroptosis-mediated recovery of motor function in SCI mice by modulating the Nrf2/GPX4 pathway in an SCI model (Ni et al., 2023). Meanwhile, RES protects human bronchial epithelial cells (BEAS-2B) from ferroptosis by acting on the ferroptosis pathway and inhibits diabetic periodontitis-induced ferroptosis in alveolar osteoblasts (Li et al., 2023c), which offers the possibility of disease treatment. Furthermore, Kosuke Kato et al. showed that quercetin and RES inhibit ferroptosis by inhibiting iron-catalyzed hydroxyl radicals and are independent of the Nrf2-ARE pathway (Kato et al., 2023).

The natural molecule Hinokitiol has a stronger iron chelating ability than DFO. Platycodone activates Nrf2, upregulates SLC7A11, GPX4, heme oxygenase-1 (HO-1) and exerts antioxidant effects (Abeydeera et al., 2022; Xi et al., 2022). The study demonstrated that the injection of flatulin in the rat MCAO model significantly inhibited ferroptosis and reduced the size of cerebral infarcts and alleviated the neurological damage after cerebral ischemia in rats, providing new insights into the IS (Jayakumar et al., 2013). Meanwhile, Hinokitiol alleviates neurological aspects of behavioural disorders caused by the neurotoxin 6-hydroxy DA (6-OHDA), providing a new treatment option for PD (Xi et al., 2022). Thus Hinokitiol holds promise for more diseases.

The natural anthraquinone derivative aloe-emodin (AE) attenuates adriamycin (the doxorubicin, DOX)-induced cardiomyocyte toxicity in H9c2 rats (He Y. et al., 2023). The researchers assessed the molecular mechanism of action of Nrf2 by Western blot, luciferase reporter gene assay, and qRT-PCR analysis, and detected the changes of intracellular ROS, and lipids by fluorescence assay. The results showed that AE could activate Nrf2, upregulate the expression of SLC7A11 and GPX4, and exhibit significant antioxidant capacity, thus reducing oxidative stress (He et al., 2023).

The bioactive steroid ester Withaferin A (WFA) modulates endothelial cell apoptosis after traumatic brain injury (Şeker Karatoprak et al., 2022). In recent years, WFA has been experimentally found to have the ability to inhibit ferroptosis and to play a role in many diseases associated with ferroptosis. It has been shown that WFA can activate the Nrf2/HO-1 pathway and reduce oxidative stress to inhibit neuronal cell injury after ICH, thus exerting neuroprotective effects. Meanwhile, the combination of WFA with Fer-1 increased this neuroprotective effect (Zhou et al., 2023), bringing new hope for ICH treatment.

Arbutin (ARB) was found to reduce ROS, and MAD accumulation, upregulate GSH, and exert a mitigating effect on alcoholic fatty liver disease (ALD) and liver injury by modulating the Nrf2/HO-1 pathway and oxidative stress. In addition, ARB can promote m6A methylation of SLC7A11 by inhibiting FTO, which in turn inhibits ferroptosis and exerts a mitigating effect on NAFLD in vitro and in vivo (Jiang et al., 2023).

Dl-3-n-butylphthalide (NBP), an extract of celery, has been widely used in stroke, dementia, and ischemic diseases. In 2022 Ye et al. suggested that injection of NBP inhibited erastin-induced accumulation of iron and ROS, downregulated TFH, and upregulated Nrf2, which in turn inhibited ferroptosis and reversed the damage to DAergic neurons (MES23.5 cells) (Ye et al., 2023).

Tetrahydroxy stilbene glycoside (TSG), an active ingredient of Polygonum tigrinum, enhances memory and locomotor activity in aged rats mainly by restoring mitochondrial function and plays a role in AD (Gao et al., 2023). In an AD rat model, TSG administration modulates the Nrf2-HO-1 pathway and protects against hippocampal neuronal damage in mice. Also TSG enhanced antioxidant capacity by activating GSH/GPX4/ROS and Keap1/Nrf2/ARE signalling pathways (Zhao et al., 2023). Recent studies have shown that BFT, a fat-soluble derivative of vitamin B1 synthesis, can also rescue cognitive deficits in mice in the APP/PS1 mouse model through activation of the Nrf2/ARE pathway (Pan et al., 2016).

In addition to the above drugs, small molecule drugs such as Dihydromyricetin (DHM) (Liang et al., 2014; Xu et al., 2023), β-Caryophyllene(BCP) (Hu et al., 2022), Forsythoside A (FA) (Zhang et al., 2024b), 15, 16-Dihydrotanshinone I (DHT) (Roth et al., 2023) (Table 1) have been demonstrated to play a role in neurological impairment-related disorders by modulating the signalling factors associated with the Nrf2 pathway. However, their specific mechanisms still need to be verified more further.

Phenotypic analysis of the HT22 cell model revealed that the diphenylbutene derivative DPT could inhibit ferroptosis (EC₅₀ = 12.0 mM) and was non-toxic. Researchers have designed and synthesised 14 DPT analogues (Fang et al., 2022) using DPT as a backbone and chemically to enhance the inhibitory activity. By analysis, it was found that 3f, 3m, and 3n exhibited stronger inhibition of ferroptosis. Next, scaffolding analysis was carried out and it was found that R1 of compound 3f was substituted with 3-OCH3 and 4-OH on the A ring, and R1 of compounds 3m and 3n was substituted with 3-OCH3 and 4-OH on both the A and B rings. A comparison of activities revealed that compound 3f was significantly more active than the latter two mentioned above. Also, the stronger ferroptosis inhibition ability and superior biological activity of compound 3f were demonstrated by morphological analysis. Further DPPH assay DPT was found to be different from RTAs such as Fer-1 and DFO but inhibited ferroptosis by up-regulating FSP1 protein levels (Fang et al., 2022). In addition, compound 3f was found to alleviate the impairment of neurological function after cerebral ischemia to a certain extent in a rat MCAO model (Fang et al., 2022), which is expected to be a new prospect for the treatment of neurological disorders.

Ginsenoside Rg1, an active component of ginseng, has been shown to protect the kidney from damage by reducing oxidative stress. Following Rg1 treatment, iron content, FTL, FTH, and MDA levels in renal tissues were significantly reduced, while GPX4, FSP1, and GSH levels were elevated (Guo et al., 2022). Recent studies have demonstrated that knocking down FSP1 eliminates the inhibitory effect of ginsenosides on ferroptosis, and the administration of ginsenosides effectively alleviates Sepsis-induced Acute Kidney Injury (SI-AKI) (Guo et al., 2023).

In vivo experiments have shown that the natural chalcone cardamonin (CAD) inhibits ferroptosis and improves cartilage damage in rats by modulating the p53/SLC7A11/GPX4 signaling pathway. Additionally, CAD has been found to have a similar effect as DFO in osteoarthritis (OA), with CAD being more effective in improving cartilage damage in OA (Gong et al., 2023).

With the development of stem cell research, the use of neural stem cells (NSCs) in the treatment of diseases is now of great interest. It has been found that exogenous NSCs can repair damaged tissues and play a role in neurological diseases such as IS (Calabrese et al., 2022). In 2022, Zhai et al. introduced human umbilical cord mesenchymal stem cells (hUC-MSCs) obtained by growth factor induction into NSCs and added NSCs by adding growth factor and neuregulin1β (NRG1β) to obtain NSCs-NRG1β. They found improved neurological function and reduced area of cerebral infarction in the rats injected with NSCs-10 nM NRG1β group in the rat MCAO/R model, and they also found an increase in the levels of GPX4 and SLC7A11 and a downregulation of p53 expression (Zhai et al., 2022). 2023, they obtained the same results with NSCs-10 nM NRG1β intervention in oxygen OGD/R-injured PC12 cells (Zhai et al., 2023). Thus NSCs provide a new direction for the future treatment of neurological diseases. However, many issues including ethical issues, therapeutic efficacy, and safety of exogenous NSC transplantation remain to be resolved.

To address the problems of antioxidant enzymes in IS therapy, in 2022, Wang et al. designed an albumin-conditioned nanoparticle based on co-encapsulation with antioxidases catalase (CAT) and superoxide dismutase 1 (SOD1) in a “neutrophil piggybacking” strategy. In the MCAO model, Neutrophil therapy delivered SOD1/CAT and Se to the site of brain injury in mice and significantly alleviated the area of cerebral infarction in mice after IS (Wang et al., 2022). In addition, the delivery of Se successfully upregulated GPX4 expression. At the same time, in addition to Neutrophil therapy, macrophages and monocytes also have this delivery capacity (Wang et al., 2022). Therefore, this neutrophil piggybacking strategy holds the promise of facilitating the application of nanomedicines in the central nervous system.

The injection of DFO in a model of Idiopathic pulmonary fibrosis (IPF) was found to increase survival (from 50% to 90%) and reverse the IPF phenotype in mice. However, low solubility and low targeting during drug delivery remain an insurmountable gap in DFO therapy. To solve this problem, the researchers prepared DFO nanomedicines and used a pulmonary drug-delivery system (PDDS) instead of oral administration or injection, and the biological effect of the drugs was significantly improved (Devkota et al., 2021).

The miR-134-5p inhibitor proposed by the investigators for the treatment of bronchopulmonary dysplasia (BPD) achieves a certain therapeutic effect, but it still suffers from the problems of conventional drugs such as drop targeting and low solubility. To better improve drug utilisation, the investigators further designed and synthesised the targeted ROS-responsive nanocarrier PCC-R8-ROS@miR-134-5p inhibitor (Lan et al., 2023), which more efficiently delivered the miR-134-5p inhibitor to the alveolar epithelial cells, providing a more efficient therapeutic strategy for BPD. However, in the future, improving encapsulation efficiency may remain a major challenge for delivering miRNAs.

AKI, a severe syndrome of renal insufficiency, was the focus of a study by Wang et al., 2021. They developed ultrasmall KCa(H₂O)₂ [FeIII(CN)₆]-H₂O nanoparticles, known as CaPB nano-enzymes, to function as a multienzymatic mimic. These nano-enzymes were effective in inhibiting ferroptosis by scavenging reactive oxygen/nitrogen species (RO/NSs) and treating AKI. The study found that CaPB nano-enzymes upregulated GPX4 both in vivo and ex vivo post intravenous administration, leading to kidney protection from oxidative damage and improved drug efficiency and targeting. Furthermore, the potential clinical application of CaPB nano-enzymes in AKI and other RO/NSs-related kidney diseases was highlighted. Xie et al., 2022 also contributed to the field by introducing gallic acid-gallium polyvinyl pyrrolidone nanoparticles (GGP NPs) as iron removers that could reduce intracellular free iron and mitochondrial dysfunction. These nanoparticles were able to downregulate iron-death-related substances like NADPH, GSH, GPX4, and ferritin, effectively suppressing ferroptosis-mediated AKI. Additionally, GGP NPs showed promise in ameliorating renal tubular injury and mitochondrial damage.

ICH remains an important cause of morbidity and mortality worldwide. Wang et al. presented a magnetically targeted nanocarrier loaded with the PPARγ agonist 15d-PGJ2-MNPs, which, when administered intravenously, activated PPARγ receptors on macrophages around haematomas, attenuated brain damage, and improved sensory and motor functions in mice after ICH (Wang et al., 2023). In addition, Yang et al. found that curcumin nanoparticles (Curcumin-NPs, Cur-NPs) could be effective in Cur delivery and provide ideas for the treatment of neurological impairment after ICH (Yang et al., 2021).

IS, a prevalent clinical neurological disorder, constitutes 85% of all strokes globally. Li et al., 2022 demonstrated that poly (lactic acid)-glycolic acid copolymerization-nanoparticles (SOD-PLGA-NPs) possess potent free radical scavenging capabilities, reducing cerebral infarct size in mice post-IS and ameliorating neurological deficits resulting from cerebral ischemia in the MCAO mouse model. Moreover, the nano delivery system enhances drug penetration through the blood-brain barrier.

Acute Liver Injury, a rare and life-threatening condition, was addressed by Shan et al. through the synthesis of ultrasmall poly (acrylic) acid coated Mn3O4 nanoparticles (PAA@Mn3O4-NPs, PMO), which effectively scavenge ROS, inhibit lipid peroxidation and ferroptosis, and mitigate Acute Liver Injury induced by acetaminophen and ischemia/reperfusion in mice. Furthermore, intravenous administration of PMO exhibits superior biocompatibility (Shan et al., 2023).

Myocardial Injury is a common complication of sepsis. Liu et al. designed and synthesised small biocompatible and MRI-visible melanin nanoparticles (MMPP) that could attenuate myocardial Injury. In ex vivo experiments, the investigators found that MMPP scavenges ROS and inhibits ferroptosis-mediated cardiomyocyte injury. In addition, MMPP downregulates oxidative stress induced by inflammatory factors (Alcalá-Alcalá et al., 2023).

Retinal pigment epithelial cells (RPE) are essential for maintaining the normal function and survival of photoreceptor cells. Oxidative stress and ferrous ion accumulation play a role in retinal degenerative diseases. Tang et al. found that a potent iron-conjugated nanoscale Prussian blue analogue, KCa [FeIII(CN)₆] (CaPB), rescued retinal structure and visual function by preventing RPE degradation and was effective in preventing RPE lesions in mouse models (Tang et al., 2021).

The current use of targeted nanotechnology has to some extent improved the problems of traditional drug targeting, solubility, and time window. Recent studies have reported that targeted nanotechnology in combination with conventional drugs has improved drug targeting even further. In a rat model of cerebral ischemia-induced neurological impairment, the co-administration of tissue plasminogen activator (tPA) with nanoliposomal Fasudil-Lip showed better neuroprotection, and prolonged therapeutic time window (TTW) and improved drug targeting (Fukuta et al., 2017). Therefore, we can speculate whether ferroptosis inhibitors could also better address issues such as drug targeting by combining them with nanoliposome-encapsulated drugs.