Ferroptosis is a regulated, iron-dependent form of cell death driven by lipid peroxidation and distinct from apoptosis, necroptosis, and pyroptosis. Recent studies implicate ferroptosis as a central contributor to the pathogenesis of renal fibrosis, a hallmark of chronic kidney disease associated with high morbidity and progression to end-stage renal failure. This review synthesizes current evidence linking ferroptotic signaling to fibrotic remodeling in the kidney, focusing on iron metabolism dysregulation, glutathione peroxidase 4 (GPX4) inactivation, lipid peroxide accumulation, and ferroptosis-regulatory pathways such as FSP1-CoQ10-NAD(P)H and GCH1-BH4. We detail how ferroptosis in tubular epithelial cells modulates pro-fibrotic cytokine release, macrophage recruitment, and TGF-β1-driven extracellular matrix deposition. Moreover, we explore ferroptosis as a therapeutic vulnerability in renal fibrosis, highlighting promising agents including iron chelators, GPX4 activators, anti-lipid peroxidants, and exosome-based gene delivery systems. By consolidating emerging preclinical data, this review provides a comprehensive mechanistic framework and identifies translational opportunities for targeting ferroptosis in fibrotic kidney disease.

Ferroptosis suppressor protein 1 (FSP1) is a recently identified ferroptosis suppressor that functions independently of the glutathione peroxidase reductase 4 (GPX4)-mediated pathway. Mechanistically, FSP1 mitigates ferroptosis by catalyzing the reduction of ubiquinone to ubiquinol and vitamin K (VK) to hydroquinone, thereby reducing lethal lipid peroxidation through the neutralization of free radicals. In this study, we designed and synthesized 32 compounds to systematically explore their structure-activity relationship (SAR) with the aim of identifying potent and novel FSP1 inhibitors. Among these, compound 39, a triazolothiadiazole derivative, exhibited the most significant inhibitory activity against FSP1, with an IC50 value of 35 nM. In vitro cellular assays demonstrated that compound 39 markedly enhanced RSL3-induced lipid peroxide (LPO) accumulation and sensitized cancer cells from diverse tissue origins to RSL3-induced ferroptosis. Furthermore, by exploiting the FSP1-mediated reduction of VK, compound 39 effectively augmented ferroptosis in HT1080 cells pretreated with RSL3 and VK through its potent inhibition of FSP1 activity. To the best of our knowledge, this study represents the first pharmacochemical investigation dedicated to the systematic design and synthesis of FSP1 inhibitors. Collectively, our findings underscore the profound impact of compound 39 on tumor ferroptosis, providing a promising foundation for the development of FSP1 inhibitors as potential therapeutic agents in cancer treatment.

The discovery of ferroptosis has brought a revolutionary breakthrough in heart failure treatment, and natural products, as a significant source of drug discovery, are gradually demonstrating their extraordinary potential in regulating ferroptosis and alleviating heart failure symptoms. In addition to chemically synthesized small molecule compounds, natural products have attracted attention as an important source for discovering compounds that target ferroptosis in treating heart failure.

Systematically summarize and analyze the research progress on improving heart failure through natural products' modulation of the ferroptosis pathway.

By comprehensively searching authoritative databases like PubMed, Web of Science, and China National Knowledge Infrastructure with keywords such as "heart failure", "cardiovascular disease", "heart disease", "ferroptosis", "natural products", "active compounds", "traditional Chinese medicine formulas", "traditional Chinese medicine", and "acupuncture", we aim to systematically review the mechanism of ferroptosis and its link with heart failure. We also want to explore natural small-molecule compounds, traditional Chinese medicine formulas, and acupuncture therapies that can inhibit ferroptosis to improve heart failure.

In this review, we not only trace the evolution of the concept of ferroptosis and clearly distinguish it from other forms of cell death but also establish a comprehensive theoretical framework encompassing core mechanisms such as iron overload and system xc-/GSH/GPX4 imbalance, along with multiple auxiliary pathways. On this basis, we innovatively link ferroptosis with various types of heart failure, covering classic heart failure types and extending our research to pre-heart failure conditions such as arrhythmia and aortic aneurysm, providing new insights for early intervention in heart failure. Importantly, this article systematically integrates multiple strategies of natural products for interfering with ferroptosis, ranging from monomeric compounds and bioactive components to crude extracts and further to traditional Chinese medicine formulae. In addition, non-pharmacological means such as acupuncture are also included.

This study fills the gap in the systematic description of the relationship between ferroptosis and heart failure and the therapeutic strategies of natural products, aiming to provide patients with more diverse treatment options and promote the development of the heart failure treatment field.

Ferroptosis is a form of regulated cell death characterized by iron accumulation and increased lipid peroxidation, primarily counteracted by a range of antioxidant molecules, including glutathione (GSH), glutathione peroxidase 4 (GPX4), ubiquinone, tetrahydrofolate, and nuclear respiratory factor 2. Furthermore, the process of ferroptosis is intricately influenced by the opposing actions of the p53 tumor suppressor gene and activated transcription factors 3 and 4, which can either facilitate or hinder ferroptotic cell death depending on the cellular context. This form of cell death is significantly associated with various pancreatic disorders, including both acute and chronic pancreatitis, as well as diabetes mellitus. In this review, we thoroughly investigate the mechanisms underlying ferroptosis, focusing on iron overload, lipid peroxidation, and the regulatory molecules involved in ferroptosis modulation (notably the system xc-/GSH/GPX4 axis), along with the relevant signaling pathways. We also examine the role of ferroptosis in non-neoplastic pancreatic diseases such as pancreatitis and diabetes mellitus while identifying novel therapeutic agents that target ferroptosis, potentially paving the way for innovative treatment strategies for pancreatic conditions.

Menaquinone (MK), which is also known as vitamin K2, is a kind of lipoquinone that, unlike humans, is biosynthesized in bacteria through a series of steps as a necessary component of their respiratory chain for electron transport among various components of the bacterial cell membrane. MKs are receiving increasing attention as they play several essential biological roles in humans.

In this study, MK was obtained from Kocuria sp. RAM1, characterized using UV absorbance, and validated using nuclear magnetic resonance spectroscopy (NMR) and liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry (LC-ESI-QTOF-MS). The chemical characterization revealed a total of six MK analogues that were identified and confirmed as MK-1, MK-3, MK-5 (H2), MK-7 (H6), MK-8 (H2), and MK-9. Subsequent to the execution of a significant optimization model, a total KMs of 394.69 µg/ml was obtained, with the MK-1 analog being the dominant one. The antibacterial, anti-inflammatory, antioxidant, anticancer, antidiabetic, and wound-healing activities of MKs were evaluated in vitro. As a result, we discovered that MKs have promising findings on the tested in vitro activities.

Our study was made to evaluate MKs obtained from the Red Sea Kocuria sp. RAM1 to emphasize their significant role in different biological applications. Therefore, from a therapeutic and medicinal perspective, the extracted MKs are interesting for additional in vivo studies.

While the plasma phylloquinone (PK) concentration is inversely correlated with cardiovascular risk, the involvement of PK in regulating endothelial function has not been directly investigated. Therefore, in this study we assessed the effects of short-term treatment with PK-deficient diets (5-10 weeks) on endothelial function in normolipidemic 14-week-old male C57BL/6JCmd mice and age-matched dyslipidaemic male E3L.CETP mice. Our results show that in normolipidemic mice dietary PK deficiency was associated with a marked reduction of PK levels in the plasma and liver (liquid chromatography-mass spectrometry measurements) and with impaired endothelium-dependent vasodilation assessed in vivo by magnetic resonance imaging (MRI). Dietary PK deficiency-induced endothelial dysfunction was fully reversed by PK supplementation. In dyslipidaemic E3L.CETP mice, dietary PK deficiency exacerbated preexisting endothelial dysfunction. Furthermore, dietary PK deficiency decreased menaquinone-4 (MK-4) levels in the aorta but did not affect blood coagulation (calibrated automated thrombography), microbiota composition (culturing and next-generation sequencing), and gut menaquinone production. In conclusion, our study demonstrated for the first time that sufficient dietary PK intake supports endothelial function in normolipidemic and dyslipidaemic mice indicating nutritional significance of dietary PK in the maintenance of endothelial function in humans.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly prevalent condition and a major risk factor for chronic liver damage, potentially leading to steatohepatitis and HCC. It is already known that patients with MASLD show increased systemic and hepatic iron concentrations as well as perturbed lipid metabolism, suggesting the involvement of ferroptosis in the development and progression of MASLD. Consequently, inhibition of ferroptosis represents a potential therapeutic option for patients with MASLD.

We investigated whether liver parenchymal cell-specific deletion (LPC-KO) of the pro-ferroptotic gene acyl-CoA synthetase long-chain family member 4 (ACSL4LPC-KO) reduces MASLD onset and progression in mice. ACSL4LPC-KO and wild-type littermates were fed a choline-deficient high-fat diet (CD-HFD) or a Western diet for 20 weeks (CD-HFD and Western diet) or 40 weeks (CD-HFD only) to monitor MASLD progression and metabolic syndrome development.

In contrast to the recently published studies by Duan et al, our results show no significant differences between ACSL4LPC-KO and wild-type mice with regard to the development of MASLD or the progression of metabolic syndrome. Furthermore, no differences were observed in metabolic parameters (ie, weight gain, glucose tolerance test, hepatic steatosis) or MASLD-associated inflammatory response.

Our analyses, therefore, suggest that loss of ACSL4 has no effect on the progression of MASLD induced by CD-HFD or the Western diet. The discrepancy between our and previously published results could be due to differences in the diets or the influence of a distinct microbiome, so the results obtained with hepatocyte-specific ACSL4LPC-KO should be taken with caution.

Vitamins are vital nutrients essential for metabolism, functioning as coenzymes, antioxidants, and regulators of gene expression. Their absorption and metabolism rely on specialized transport proteins that ensure bioavailability and cellular utilization. Water-soluble vitamins, including B-complex and vitamin C, are transported by solute carrier (SLC) family proteins and ATP-binding cassette (ABC) transporters for efficient uptake and cellular distribution. Fat-soluble vitamins (A, D, E, and K) rely on lipid-mediated pathways through proteins like scavenger receptor class B type I (SR-BI), CD36, and Niemann-Pick C1-like 1 (NPC1L1), integrating their absorption with lipid metabolism. Defective vitamin transporters are associated with diverse metabolic disorders, including neurological, hematological, and mitochondrial diseases. Advances in structural and functional studies of vitamin transporters highlight their tissue-specific roles and regulatory mechanisms, shedding light on their impact on health and disease. This review emphasizes the significance of vitamin transporters and their potential as therapeutic targets for deficiencies and related chronic conditions.

Ferroptosis is a regulated form of cell death characterised by iron-dependent lipid peroxidation, a process intricately linked to cellular redox homeostasis. This form of cell death is induced by the accumulation of intracellular iron and the subsequent generation of reactive oxygen species (ROS), which leads to lipid peroxidation and ultimately cell death. Ferroptosis is distinct from traditional forms of cell death, such as apoptosis, and holds significant therapeutic potential, particularly in cancers harboring rat sarcoma virus (RAS) mutations, such as epithelial ovarian cancer (EOC). EOC is notoriously resistant to conventional therapies and is associated with a poor prognosis. In this review, we examine recent progress in the understanding of ferroptosis, with a particular focus on its redox biology and the complex regulatory networks involved. We also propose a novel classification system for ferroptosis modulators, grouping them into six categories (I, II, III, IV, V and VI) based on their mechanisms of action and their roles in modulating cellular redox status. By refining these categories, we aim to provide deeper insights into the role of ferroptosis in cancer biology, especially in EOC, and to identify potential therapeutic avenues. We propose that further investigation of ferroptosis in the context of redox biology could reveal novel biomarkers and therapeutic targets, offering promising strategies to overcome resistance mechanisms and improve clinical outcomes for patients with EOC and other treatment-resistant cancers.

Excessive reactive oxygen species (ROS) levels cause oxidative stress, which can lead to various diseases. Renal failure is associated with oxidative stress and mitochondrial dysfunction. Vitamin K1 (phylloquinone) and K2 (menaquinone) are essential for blood coagulation and bone formation. Vitamin K has been shown to have anti-inflammation, glucose metabolism regulation, and antiferroptosis functions. We investigated the impact of menaquinone-4 (MK-4) on oxidative stress and mitochondrial dysfunction in human renal proximal tubular cells. MK-4 protected cells from oxidative damage induced by l-buthionine-(S,R)-sulfoximine (BSO), a selective inhibitor of glutathione metabolism, by inhibiting cell death, mitochondrial ROS production, and lipid peroxidation. MK-4 also reduced lactate production, prevented mitochondrial fragmentation, and improved mitochondrial respiratory function, indicating cytoprotective effects. Moreover, it enhanced intracellular ATP production and respiratory capacity, even in the absence of oxidative stress. Thus, MK-4 plays an important role in mitochondrial function in renal proximal tubular cells.

Ferroptosis is a type of cell death process defined by iron-dependent peroxidation of phospholipids leading to the destruction of cellular membranes and death of the cell. Ferroptosis occurs throughout the body, but a considerable research focus on ferroptosis in the brain - neuroferroptosis - has been driven by the rich lipid and iron content of the brain as well as its high oxygen consumption. Neurons also have an exceptionally large surface area and metabolic demand, which necessitates specific mechanisms (such as lipid antioxidants) to engage constantly to protect the plasma membrane against lipid peroxidation. Ferroptosis has been extensively linked to neurodegeneration and ischaemia and is increasingly implicated in physiological processes such as neuronal reprogramming. Astrocytes provide metabolic support to neurons, enabling them to defend against ferroptosis, yet ferroptotic signals in microglia can propagate damage to astrocytes and neurons, highlighting the complex intercellular (patho)physiology of neuroferroptosis.

Ferroptosis is a form of cell death due to iron-induced lipid peroxidation. Ferroptosis suppressor protein 1 (FSP1) protects against this death by generating antioxidants, which requires nicotinamide adenine dinucleotide, reduced form (NADH) as a cofactor. We initially uncover that NADH exists at significant levels on cellular membranes and then find that this form of NADH is generated by aldehyde dehydrogenase 7A1 (ALDH7A1) to support FSP1 activity. ALDH7A1 activity also acts directly to decrease lipid peroxidation by consuming reactive aldehydes. Furthermore, ALDH7A1 promotes the membrane recruitment of FSP1, which is instigated by ferroptotic stress activating AMP-activated protein kinase (AMPK) to promote the membrane localization of ALDH7A1 that stabilizes FSP1 on membranes. These findings advance a fundamental understanding of NADH by revealing a previously unappreciated pool on cellular membranes, with the elucidation of its function providing a major understanding of how FSP1 acts and how an aldehyde dehydrogenase protects against ferroptosis.

N-acetyl-l-cysteine (NAC) is a medication and a widely used antioxidant in cell death research. Despite its somewhat obscure mechanism of action, its role in inhibiting ferroptosis is gaining increasing recognition. In this study, we demonstrate that NAC treatment rapidly replenishes the intracellular cysteine pool, reinforcing its function as a prodrug for cysteine. Interestingly, its enantiomer, N-acetyl-d-cysteine (d-NAC), which cannot be converted into cysteine, also exhibits a strong anti-ferroptotic effect. We further clarify that NAC, d-NAC, and cysteine all act as direct reducing substrates for GPX4, counteracting lipid peroxidation. Consequently, only GPX4-rather than system xc-, glutathione biosynthesis, or ferroptosis suppressor protein 1-is necessary for NAC and d-NAC to prevent ferroptosis. Additionally, we identify a broad range of reducing substrates for GPX4 in vitro, including β-mercaptoethanol. These findings provide new insights into the mechanisms underlying the protective effects of NAC and other potential GPX4-reducing substrates against ferroptosis.

Ferroptosis is a newly identified cell death triggered by iron-induced lipid peroxidation. Numerous studies reveal that ferroptosis participates in multiple types of tissue injury including ischaemia-reperfusion (I/R) injury and doxorubicin (Dox)-induced damage. Targeting ferroptosis is a promising approach for disease treatment as the blockade of ferroptosis efficiently alleviates the symptoms. However, no known ferroptosis inhibitors have been used for clinical treatment. Although certain clinical compounds act as ferroptosis inhibitors in vitro, whether these drugs cure tissue injury by suppressing ferroptosis is little known. Here, by screening a large panel of drugs used in the clinic, it is identified that dipyridamole significantly attenuates Dox or I/R-induced cardiac injury. Moreover, dipyridamole can achieve a good therapeutic effect on  liver and kidney injury. Mechanistically, dipyridamole-mediated ferroptosis inhibition is strictly dependent on solute carrier family 7 member 11 (SLC7A11). Dipyridamole down-regulates the expression of ring finger protein 126 (RNF126), which is an E3 ligase to ubiquitinate SLC7A11 for proteasome degradation. Deficiency of SLC7A11 largely blocks the protective role of dipyridamole in vitro and in vivo. Together, the findings uncover that dipyridamole acts as a clinical compound to alleviate organ injury via suppressing ferroptosis, providing novel insights into the clinical therapy for ferroptosis-related tissue damage.

The discovery and conceptualization of ferroptosis as regulated, iron-catalyzed cell death driven by excessive lipid peroxidation triggered re-evaluation of lipid hydroperoxides in connection with health and disease. Free and ester forms of polyunsaturated fatty acids (PUFAs) are oxidized in vivo by multiple oxidizing species to produce lipid hydroperoxides as primary products, some purposely while others unintentionally. The detailed analysis of isomer distribution of lipid hydroperoxides enables us to identify the responsible oxidants. Linoleates, the most abundant PUFA in humans, are oxidized to give multiple isomers of hydroperoxyoctadecadienoates (H(p)ODEs) as primary major products, racemic trans, trans-9- and 13-H(p)ODEs, 13(S)-cis, trans-H(p)ODE, and 10- and 12-H(p)ODEs being specific biomarker for the oxidation by free radicals, lipoxygenase (LOX), and singlet oxygen, respectively. Cholesterol is another important lipid and its hydroperoxides are produced solely by non-enzymatic oxidation, the major products being cholesterol 7-hydroperoxide and 5-hydroperoxide by free radicals and singlet oxygen, respectively. The available data obtained from human samples show that lipid hydroperoxides are produced in vivo primarily by free radical mediated lipid peroxidation and that the contribution of LOXs s and singlet oxygen is small. Multiple antioxidants having different functions play their respective roles in the physiological defense network against detrimental lipid peroxidation and ferroptosis. The fact that lipid hydroperoxides are produced in vivo mainly by free radical mediated lipid peroxidation suggests that radical scavenging antioxidants act as essential ferroptosis inhibitors, which was substantiated by many studies. Considering the reactivity and physiological concentrations, it may be said that vitamins E and C play the primary roles as biological radical scavenging antioxidants against ferroptosis by synergistic interactions. Novel synthetic antioxidants with higher reactivity than natural antioxidants have been reported and their biological effects should be assessed. The factors that determine antioxidant effects in vivo are critically reviewed.

The ferroptosis of cardiomyocytes has been recognized as the core pathological mechanism of heart failure. During the evolution of cardiovascular diseases, the accumulation of angiotensin II and advanced glycation end products can lead to the excessive activation of the RAGE/TLR4-JNK1/2 pathway, which subsequently triggers ferritinophagy, clockophagy, and enhanced p53 activity, ultimately leading to cardiomyocyte ferroptosis. It is evident that deeply unraveling the specific mechanisms in this field and comprehensively evaluating potential drugs and therapeutic strategies targeting this pathway is crucial for improving the status of cardiomyocyte ferroptosis. However, our current understanding of this pathway's specific molecular biological mechanisms in the process of cardiomyocyte ferroptosis remains limited. In light of this, this paper first comprehensively reviews the historical context of ferroptosis research, compares the similarities and differences between ferroptosis and other standard modes of cell death, elucidates the core mechanisms of ferroptosis and its close connection with heart failure, aiming to establish a basic cognitive framework for readers on ferroptosis and its role in heart failure. Subsequently, the paper delves into the pivotal role of the RAGE/TLR4-JNK1/2 pathway in cardiomyocyte ferroptosis and its intricate molecular biological regulatory network. Furthermore, it systematically integrates various therapeutic approaches aimed at inhibiting RAGE, TLR4, and JNK1/2 activity to alleviate cardiomyocyte ferroptosis, encompassing RNA interference technology, gene knockout techniques, small molecule inhibitors, natural active ingredients, as well as traditional Chinese and Western medicines, with the ultimate goal of forging new avenues and strategies for the prevention and treatment of heart failure.

Menaquinone 4 (MK-4) is the primary form of vitamin K found in the brain. In rodent studies, treatment with the vitamin K antagonist warfarin lowered brain MK-4 concentrations. It is not known if brain MK-4 levels are influenced by warfarin treatment in humans. To address this, we compared post-mortem brain MK-4 concentrations in older adults treated with warfarin prior to death to older adults not treated with warfarin. We also determined the likelihood of having mild cognitive impairment (MCI) or dementia in warfarin users, compared to non-users.

We utilized data from 381 autopsied participants (76% female, mean±SD age at death 92±6 years) in the Rush Memory and Aging Project (MAP) in whom MK-4 was measured in 4 brain regions: mid-frontal and temporal cortices, anterior watershed (AWS), and cerebellum. Brain MK-4 concentrations were compared between those treated with warfarin and those not treated, using linear regression adjusted for age, sex, and cognitive diagnosis at death. The association of warfarin use prior to death with cognitive diagnosis at death was evaluated using logistic regression, adjusted for age, sex, education, and apoE4 status.

Warfarin users (n=73, median (IQR) duration of warfarin use = 585 (479-656) days) had 68-79% lower brain MK-4 concentrations in all measured regions, including the mean across all regions, compared to non-warfarin users (unstandardized β -1.538 to -1.140; all p<.001, fully adjusted). The likelihood of having MCI or dementia, versus no cognitive impairment, at death did not significantly differ between those treated with warfarin prior to death and those not [OR (95%CI) for MCI: 0.82 (0.41, 1.62), dementia: 1.04 (0.57, 1.93), fully adjusted].

These findings suggest that warfarin treatment influences MK-4 concentrations in the human brain. Future studies are needed to elucidate the mechanisms underlying this effect and the clinical implications.

Flavoprotein quinone reductases regenerate quinols which serve metabolic and antioxidant roles. These enzymes catalyze the two-electron oxidation of substrates and the subsequent two electron reduction of quinones. Despite the net two electron transfer between substrates, the binding mode of quinones is typically end-on to the flavin, rather than stacked, dictating that the oxidative half reaction cannot proceed via hydride transfer and must instead occur by two successive single electron transfers. Here we present a review of six of the most well-studied flavoprotein quinone reductases to establish a framework for discussing this positional orientation for the quinone oxidant. There are two non-mutually exclusive rationalizations for this binding mode where the flavin isoalloxazine acts as a redox partition. The first is that energetics of the single electron transfer pathway create a kinetic barrier to the reverse reaction, trapping electrons in the quinone pool and countering the high ratio of quinol to quinone present in the membrane. The second is that the end-on binding allows the enzymes to utilize different binding sites for cytosolic and membrane associated substrates, avoiding the need to desorb substrates. These effects may be additive and serve to funnel electrons into the quinone pool as efficiently as possible.

Ferroptosis is an emerging form of programmed cell death triggered by iron-dependent lipid peroxidation. It is distinguished from other forms of cell death by its unique morphological changes and characteristic fine-tuned regulatory gene network. Since its pivotal involvement in the pathogenesis and therapeutic interventions of various diseases, such as malignant tumors, cardiovascular and cerebrovascular diseases, and traumatic disorders, has been well-established, ferroptosis has garnered significant attention in contemporary physiological and pathological research. For the advantage of alleviating the clinical symptoms and improving life quality, traditional Chinese medicine (TCM) holds a significant position in the treatment of these ailments. Moreover, increasing studies revealed that TCM compounds and monomers showed evident therapeutic efficacy by regulating ferroptosis via signaling pathways that tightly regulate redox reactions, iron ion homeostasis, lipid peroxidation, and glutathione metabolism. In this paper, we summarized the current knowledge of TCM compounds and monomers in regulating ferroptosis, aiming to provide a comprehensive review of disease management by TCM decoction, Chinese patent medicine, and natural products deriving from TCM through ferroptosis modulation. The formulation composition, chemical structure, and possible targets or mechanisms presented here offer valuable insights into the advancement of TCM exploration.

The outcome after liver transplantation has improved in recent years, which can be attributed to superior storage and transportation conditions of the organs, as well as better peri- and postoperative management and advancements in surgical techniques. Nevertheless, there is an increasing discrepancy between the need for organs and their availability. Consequently, the mortality rate on the waiting list is high and continues to rise. One way of counteracting this trend is to increase the use of "expanded criteria donors." This means that more and more donors will be included, especially those who are older and having additional comorbidities (eg, steatosis). A major complication of any transplantation is the occurrence of ischemia/reperfusion injury (IRI), which often leads to liver dysfunction and failure. However, there have been various promising approaches to minimize IRI in recent years, but an effective and clinically applicable method to achieve a better outcome for patients after liver transplantation is still missing. Thereby, the so-called marginal organs are predominantly affected by IRI; thus, it is crucial to develop suitable and effective treatment options for patients. Recently, regulated cell death mechanisms, particularly ferroptosis, have been implicated to play a major role in IRI, including the liver. Therefore, inhibiting this kind of cell death modality presents a promising therapeutic approach for the management of this yet untreatable condition. Thus, this review provides an overview of the role of ferroptosis in liver IRI and transplantation and discusses possible therapeutic solutions based on ferroptosis inhibition to restrain IRI in marginal organs (especially steatosis and donation after circulatory death organs).

Ferroptosis and apoptosis are widely considered to be independent cell death modalities. Ferroptotic cell death is a consequence of insufficient radical detoxification and progressive lipid peroxidation, which is counteracted by glutathione peroxidase-4 (GPX4). Apoptotic cell death can be triggered by a wide variety of stresses, including oxygen radicals, and can be suppressed by anti-apoptotic members of the BCL-2 protein family. Mitochondria are the main interaction site of BCL-2 family members and likewise a major source of oxygen radical stress. We therefore studied if ferroptosis and apoptosis might intersect and possibly interfere with one another. Indeed, cells dying from impaired GPX4 activity displayed hallmarks of both ferroptotic and apoptotic cell death, with the latter including (transient) membrane blebbing, submaximal cytochrome-c release and caspase activation. Targeting BCL-2, MCL-1 or BCL-XL with BH3-mimetics under conditions of moderate ferroptotic stress in many cases synergistically enhanced overall cell death and frequently skewed primarily ferroptotic into apoptotic outcomes. Surprisingly though, in other cases BH3-mimetics, most notably the BCL-XL inhibitor WEHI-539, counter-intuitively suppressed cell death and promoted cell survival following GPX4 inhibition. Further studies revealed that most BH3-mimetics possess previously undescribed antioxidant activities that counteract ferroptotic cell death at commonly employed concentration ranges. Our results therefore show that ferroptosis and apoptosis can intersect. We also show that combining ferroptotic stress with BH3-mimetics, context-dependently can either enhance and convert cell death outcomes between ferroptosis and apoptosis or can also suppress cell death by intrinsic antioxidant activities.

Ovarian cancer, a gynecologic malignancy with high mortality rates, faces persistent therapeutic challenges due to acquired resistance and frequent recurrence with conventional therapies. While poly (ADP-ribose) polymerase (PARP) inhibitors have primarily transformed clinical outcomes through the synthetic lethality mechanism, their long-term efficacy remains constrained by therapeutic resistance. Ferroptosis, a novel programmed cell death modality characterized by iron-dependent lipid peroxidation, has emerged as a promising therapeutic frontier in oncology. This review is the first to summarize the mechanisms of action and resistance associated with both ferroptosis and PARP inhibitors in ovarian cancer.

Solid organ transplantation is hampered by complications that arise after ischemia-reperfusion injury (IRI), a detrimental type of injury for which no adequate treatment options are available. Ferroptosis, an iron-dependent form of regulated cell death, is a major driver of IRI. This systematic review and meta-analysis summarizes the effects of pharmacological ferroptosis inhibition in abdominal organs in the setting of IRI. PubMed, Embase, Web of Science and Cochrane were searched for concepts "ferroptosis" and "IRI" in August 2023. To allow for meta-analyses, inhibitors were divided into different intervention pathways: (I) lipophilic radical scavengers, (II) iron chelators, (III) antioxidants, (IV) lipid metabolism inhibitors, (V) combination treatments, and (VI) others. When available, organ function and injury effect sizes were extracted and used for random-effects meta-analyses. In total 79 articles were included, describing 59 unique inhibitors in kidney, liver, and intestinal IRI. No studies in pancreas were found. Overall bias and study quality was unclear and average to low, respectively. Apart from 1 clinical study, all inhibitors were tested in preclinical settings. The vast majority of the studies showed ferroptosis inhibition to be protective against IRI under various treatment conditions. In liver and kidney IRI, meta-analyses on standardized effect sizes from 43 articles showed a combined protective effect against IRI compared with a nontreated controls for all analyzed intervention pathways. In conclusion, ferroptosis inhibition protects against abdominal IRI in preclinical research. Important questions regarding optimal intervention pathway, bioavailability, optimal dosage, side effects etc. should be addressed before clinical introduction.

Since its introduction in 2012, ferroptosis has garnered significant attention from researchers over the past decade. Unlike autophagy and apoptosis, ferroptosis is an atypical iron-dependent programmed cell death that falls under necrosis. It is regulated by various cellular metabolic and signaling processes, which encompass amino acid, lipid, iron, and mitochondrial metabolism. The initiation of ferroptosis occurs through iron-dependent phospholipid peroxidation. Notably, ferroptosis exhibits a dual effect and is associated with various diseases. A significant challenge lies in managing autoimmune disorders with unknown origins that stem from the reactivation of the immune system. Two contributing factors to autoimmunity are the aberrant stimulation of cell death and the inadequate clearance of dead cells, which can expose or release intracellular components that activate the immune response. Ferroptosis is distinct from other forms of cell death, such as apoptosis, necroptosis, autophagy, and pyroptosis, due to its unique morphological, biochemical, and genetic characteristics and specific relationship with cellular iron levels. Recent studies indicate that immune cells can both induce and undergo ferroptosis. To better understand how ferroptosis influences immune responses and its imbalance in disease, a molecular understanding of the relationship between ferroptosis and immunity is essential. Consequently, further research is needed to develop immunotherapeutics that target ferroptosis. This review primarily focuses on the role of ferroptosis in immune-related disorders.

This study aims to explore the therapeutic potential of Angelicae Pubescentis Radix (APR), a traditional Chinese medicine that is widely known for its anti-inflammatory, anti-oxidative, and anti-microbial properties, using a mouse model. In this study, 30 mice were selected and divided into three groups: control group (CD), infection group (ED), and treatment group (TD). Mice in the TD were gavaged with APR oil (0.15 mL/kg/day) for 20 days, while mice in the CD and ED received an equal volume of normal saline. On the 21st day, mice in the ED and TD were infected with multi-drug-resistant E. coli (1 × 107 CFU/mL) derived from diarrheal yak. Twenty-four hours later, all mice were euthanized, and blood, organs, and intestinal samples were collected for analysis. The results of intestinal sections and intestinal bacterial load revealed that APR treatment significantly reduced (p < 0.05) both bacterial load and intestinal injury. Serum analysis indicated that APR treatment also alleviated the inflammation and oxidative stress induced by E. coli infection. Intestinal microbiota sequencing further showed that APR treatment increased the abundance of intestinal probiotics such as Ligilactobacillus, Paludicola, and Blautia_A_1417806 while also enhancing the enrichment of functional pathways associated with antioxidant defense. In conclusion, APR treatment effectively alleviates diseases caused by E. coli infection, promotes the growth of beneficial intestinal bacteria, and improves the antioxidant capacity in animals. Additionally, these findings confirm APR's role in addressing immediate effects rather than chronic adaptations. Future studies should investigate the prolonged effects of APR treatment beyond the acute phase.

Programmed cell death is a mechanism that is crucial for numerous physiological and pathological processes. Whereas p53-mediated apoptosis is a major cell death pathway in cancer, accumulating evidence indicates that p53 also has crucial roles in controlling different non-apoptotic cell death (NACD) pathways, including ferroptosis, necroptosis, pyroptosis, autophagy-dependent cell death, entotic cell death, parthanatos and paraptosis, and may regulate PANoptosis, cuproptosis and disulfidptosis. Notably, the function of p53 in these NACDs substantially contributes to its biological effects, particularly in cancer development and other pathological processes. In this Review, we discuss recent advances in understanding the roles and underlying mechanisms of p53-mediated NACDs, focusing on ferroptosis, necroptosis and pyroptosis. We discuss the complex and distinct physiological settings in which NACDs are regulated by p53, and potential targeting of p53-regulated NACDs for the treatment of cancer and other human diseases. Finally, we highlight several important questions concerning p53-regulated NACDs that warrant further investigation.

Ferroptosis is a necrotic, non-apoptotic cell death modality triggered by unrestrained iron-dependent lipid peroxidation. By unveiling the regulatory mechanisms of ferroptosis and its relevance to various diseases, research over the past decade has positioned ferroptosis as a promising therapeutic target. The rapid growth of this research field presents challenges, associated with potentially inadequate experimental approaches that may lead to misinterpretations in the assessment of ferroptosis. Typical examples include assessing whether an observed phenotype is indeed linked to ferroptosis, and selecting appropriate animal models and small-molecule modulators of ferroptotic cell death. This Expert Recommendation outlines state-of-the-art methods and tools to reliably study ferroptosis and increase the reproducibility and robustness of experimental results. We present highly validated compounds and animal models, and discuss their advantages and limitations. Furthermore, we provide an overview of the regulatory mechanisms and the best-studied players in ferroptosis regulation, such as GPX4, FSP1, SLC7A11 and ACSL4, discussing frequent pitfalls in experimental design and relevant guidance. These recommendations are intended for researchers at all levels, including those entering the expanding and exciting field of ferroptosis research.

Ferroptosis is an iron-dependent and oxidative form of non-apoptotic cell death with roles in development, homeostasis, and disease. Ferroptosis sensitivity can vary between cells, often for reasons that are not well understood. In this perspective, we describe the core ferroptosis mechanism and outline how changes in iron, redox, and lipid metabolism can alter ferroptosis sensitivity. We propose the concept of a ferroptosis sensitivity-resistance continuum to describe how different intrinsic and extrinsic factors interact to push cells toward a more ferroptosis-sensitive or ferroptosis-resistant state, with effects on development and diseases such as cancer.

Spinal cord injury (SCI) is a severe traumatic condition that frequently results in various neurological disabilities, including significant sensory, motor, and autonomic dysfunctions. Ferroptosis, a recently identified non-apoptotic form of cell death, is characterized by the accumulation of reactive oxygen species (ROS), intracellular iron overload, and lipid peroxidation, ultimately culminating in cell death. Recent studies have demonstrated that ferroptosis plays a critical role in the pathophysiology of SCI, contributing significantly to neural cell demise. Three key cellular enzymatic antioxidants such as glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), and dihydroorotate dehydrogenase (DHODH), have been elucidated as crucial components in the defense against ferroptosis. Natural products, which are bioactive compounds mostly derived from plants, have garnered considerable attention for their potential therapeutic effects. Numerous studies have reported that several natural products can effectively mitigate neural cell death and alleviate SCI symptoms. This review summarizes fifteen natural products containing (-)-Epigallocatechin-3-gallate (EGCG), Proanthocyanidin, Carnosic acid, Astragaloside IV, Trehalose, 8-gingerol, Quercetin, Resveratrol, Albiflorin, Alpha-tocopherol, Celastrol, Hispolon, Dendrobium Nobile Polysaccharide, Silibinin, and Tetramethylpyrazine that have shown promise in treating SCI by inhibiting ferroptosis. Additionally, this review provides an overview of the mechanisms involved in these studies and proposes several perspectives to guide future research directions.

Ferroptosis is an iron-dependent form of cell death driven by the excessive peroxidation of poly-unsaturated fatty acids (PUFAs) within membrane phospholipids. Ferroptosis is a hallmark of many diseases and preventing or inducing ferroptosis has considerable therapeutic potential. Like other forms of cell death, the pathological importance and therapeutic potential of ferroptosis is well appreciated. However, while cell death modalities such as apoptosis and necroptosis have critical physiological roles, such as in development and tissue homeostasis, whether ferroptosis has important physiological roles is largely unknown. In this regard, key questions for field are as follows: Is ferroptosis used for physiological processes? Are certain cell-types purposely adapted to be either resistant or sensitive to ferroptosis to be able to function optimally? Do physiological perturbations such as aging and diet impact ferroptosis susceptibility? Herein, we have reviewed emerging evidence that supports the idea that being able to selectively and controllably induce or resist ferroptosis is essential for development and cell function. While several factors regulate ferroptosis, it appears that the ability of cells and tissues to control their lipid composition, specifically the abundance of phospholipids containing PUFAs, is crucial for cells to be able to either resist or be sensitized to ferroptosis. Finally, aging and diets enriched in specific PUFAs lead to an increase in cellular PUFA levels which may sensitize cells to ferroptosis. Therefore, changes in dietary PUFAs or againg may impact the pathogenesis of diseases where ferroptosis is involved.

Glioma, the most common malignant tumor of the central nervous system, has a high postoperative recurrence rate. While Ciprofol is widely used as an anesthetic, its therapeutic potential in glioma treatment remains largely unexplored.

Glioma T98G cells were treated with varying concentrations of Ciprofol to assess proliferation, invasion, migration, and apoptosis via CCK-8, Transwell, and flow cytometry assays. Proteomic, phosphoproteomic, and transcriptomic analyses were performed to identify molecular targets and pathways. Molecular docking evaluated the binding of Ciprofol to key kinases, and silencing experiments validated their roles. In vivo, glioma mouse models were used to assess postoperative recurrence via tumor size, fluorescence imaging, and histological analysis.

Ciprofol inhibited glioma cell proliferation, invasion, and migration while promoting apoptosis. Proteomic analyses identified MAPK11 and PML as key mediators of Ciprofol's effects. Silencing MAPK11 impaired these effects, while in vivo experiments showed reduced postoperative recurrence via MAPK11-PML phosphorylation.

Ciprofol reduces postoperative glioma recurrence by promoting MAPK11-PML phosphorylation, providing novel molecular targets for glioma treatment and suggesting its therapeutic potential beyond anesthesia.

We present here a comprehensive update on recent advancements in the field of ferroptosis, with a particular emphasis on its metabolic underpinnings and physiological impacts. After briefly introducing landmark studies that have helped to shape the concept of ferroptosis as a distinct form of cell death, we critically evaluate the key metabolic determinants involved in its regulation. These include the metabolism of essential trace elements such as selenium and iron; amino acids such as cyst(e)ine, methionine, glutamine/glutamate, and tryptophan; and carbohydrates, covering glycolysis, the citric acid cycle, the electron transport chain, and the pentose phosphate pathway. We also delve into the mevalonate pathway and subsequent cholesterol biosynthesis, including intermediate metabolites like dimethylallyl pyrophosphate, squalene, coenzyme Q (CoQ), vitamin K, and 7-dehydrocholesterol, as well as fatty acid and phospholipid metabolism, including the biosynthesis and remodeling of ester and ether phospholipids and lipid peroxidation. Next, we highlight major ferroptosis surveillance systems, specifically the cyst(e)ine/glutathione/glutathione peroxidase 4 axis, the NAD(P)H/ferroptosis suppressor protein 1/CoQ/vitamin K system, and the guanosine triphosphate cyclohydrolase 1/tetrahydrobiopterin/dihydrofolate reductase axis. We also discuss other potential anti- and proferroptotic systems, including glutathione S-transferase P1, peroxiredoxin 6, dihydroorotate dehydrogenase, glycerol-3-phosphate dehydrogenase 2, vitamin K epoxide reductase complex subunit 1 like 1, nitric oxide, and acyl-CoA synthetase long-chain family member 4. Finally, we explore ferroptosis's physiological roles in aging, tumor suppression, and infection control, its pathological implications in tissue ischemia-reperfusion injury and neurodegeneration, and its potential therapeutic applications in cancer treatment. Existing drugs and compounds that may regulate ferroptosis in vivo are enumerated.

Glaucoma is the leading cause of irreversible blindness worldwide and encompasses a group of diseases characterized by optic nerve atrophy and visual field defects. Acute intraocular pressure (IOP) elevation is a key driver of retinal inflammation and optic nerve damage, often accompanied by microglial activation and dysregulated ferroptosis pathways. Vitamin K1, a fat-soluble vitamin, possesses anti-inflammatory and antioxidant properties, and has the potential to regulate ferroptosis. However, its mechanisms in alleviating retinal inflammation following acute IOP elevation remain unclear.

In vivo, we established a mouse model of acute ocular hypertension to evaluate the protective effects of vitamin K1 on the retina and visual function. Transcriptome sequencing was used to explore the underlying mechanisms by which vitamin K1 exerts its effects. Immunofluorescence and Western blot were used to assess retinal inflammation and observe ferroptosis in microglia. In vitro, we developed a BV2 cell OGDR model to investigate the regulatory effects of vitamin K1 on iron metabolism and inflammation in microglia.

Our findings demonstrated that acute IOP elevation led to microglial activation, along with iron overload and ferroptosis in microglia. Further analyses revealed that microglial ferroptosis was accompanied by an upregulation of inflammatory cytokine gene expression and protein levels. Vitamin K1 intervention, however, inhibited microglial ferroptosis, alleviated retinal inflammation, minimized retinal ganglion cell (RGC) loss, and protected visual function.

In conclusion, this study demonstrates that vitamin K1 exerts a protective effect by modulating microglial ferroptosis, thereby alleviating acute ocular hypertension-induced retinal inflammation.

Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular event associated with high mortality and significant morbidity. Recent studies have highlighted the emerging role of ferroptosis, a novel form of regulated cell death, in the pathogenesis of SAH. Circular RNAs (circRNAs), have been found to play essential roles in various cellular processes, including gene regulation and disease pathogenesis. The expression profile of circRNAs in neural tissues, particularly in the brain, suggests their critical role in synaptic function and neurogenesis. Moreover, the interplay between circRNAs and ferroptosis-related pathways, such as iron metabolism and lipid peroxidation, is explored in the context of SAH. Understanding the functional roles of specific circRNAs in the context of SAH may provide potential therapeutic targets to attenuate ferroptosis-associated brain injury. Furthermore, the potential of circRNAs as diagnostic biomarkers for SAH severity, prognosis, and treatment response is discussed. Overall, this review highlights the significance of studying the intricate interplay between circRNAs and ferroptosis in the context of SAH. Unraveling the mechanisms by which circRNAs modulate ferroptotic cell death may pave the way for the development of novel therapeutic strategies and diagnostic approaches for SAH management, ultimately improving patient outcomes and quality of life.

More than half of the individuals with type 2 diabetes mellitus (T2DM) are accompanied by Non-alcoholic fatty liver disease (NAFLD). This study aimed to explore the relationship between nutrient intake, lifestyle, and the risk NAFLD in patients with T2DM.

This study comprised 2110 adult patients with diabetes from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018. We employed weighted logistic regression to assess the associations between nutrient intake, lifestyle and NAFLD, while exploring potential non-linear relationships using restrictive cubic spline analysis. Additionally, we validated our findings through subgroup analyses and sensitivity analyses to ensure the robustness and reliability of our results.

Out of 2110 diabetes patients, 1743 were diagnosed with NAFLD, and 53.43 % of them were male. After adjusting for potential confounders, we found a negative correlation between Vitamin K intake and the occurrence of NAFLD in patients with T2DM (OR = 0.885 [0.829, 0.959]). This dose-response relationship was further validated through stratification analysis by tertiles of vitamin K intake. Lycopene intake is identified as a risk factor for NAFLD in patients with T2DM. Specifically, for every 100 μg of lycopene ingested, there was a 0.2 % higher likelihood of NAFLD (OR = 1.002 [1.0001, 1.005], p < 0.05). Conversely, a 0.5 % reduction in NAFLD risk was observed with the same amount of lutein intake (OR = 0.995 [0.992, 0.999], p < 0.05). Furthermore, we also found that a high-quality diet can reduce the risk of NAFLD in patients with T2DM, with an odds ratio of 0.208 (0.101, 0.430).

Increasing intake of Vitamin K and lutein, reducing intake of lycopene, and improving dietary quality may lower the risk of NAFLD in patients with T2DM.

Ferroptosis is programmed cell death induced by iron-driven lipid peroxidation. Numerous studies have shown that ferroptosis is implicated in the progression of colorectal cancer (CRC) and has emerged as a promising strategy to combat therapy-resistant CRC. While the intrinsic antiferroptotic and proferroptotic pathways in CRC cells have been well characterized, extrinsic metabolism pathways regulating ferroptosis in CRC pathogenesis remain less understood. Emerging evidence shows that gut microbial metabolism is tightly correlated with the progression of CRC. This review provides an overview of gut microbial metabolism and discusses how these metabolites derived from intestinal microflora contribute to cancer plasticity through ferroptosis. Targeting gut microbe-mediated ferroptosis is a potential approach for CRC treatment.

In the physiological state, female fertility declines with age, as evidenced by a steady decline in oocyte quantity and quality. Aging of the first organ, the ovary, is accompanied by increased oxidative stress levels in the ovary, causing a decline in the ovarian reserve and follicular atresia. Ferroptosis is a novel mode of programmed cell death discovered in recent years and is involved in the onset and development of various diseases. To investigate whether ferroptosis regulates ovarian aging, we first examined granulosa cells from patients with a normal ovarian reserve, decreased ovarian reserve (DOR), and advanced age (Aged). GPX4, a key gene involved in ferroptosis, was identified. The marker of its activity, glutathione (GSH), was significantly downregulated in granulosa cells from the DOR and Aged groups. Transmission electron microscopy confirmed abnormal changes in mitochondrial morphology in granulosa cells from the DOR and Aged groups. In vitro, granulosa cell culture results showed that ferroptosis inducers inhibited cell growth by downregulating GPX4 expression. In contrast, ferroptosis inhibitors reversed the inhibitory effects of ferroptosis on granulosa cell growth by upregulating GPX4 expression. The results of mice in vivo experiments showed that the expression level of GPX4 was significantly decreased in the oocytes of aged mice and that Fer-1, an inhibitor of ferroptosis, reversed the decrease in the number of oocytes retrieved and the quality of oocytes in aged mice. Cyclophosphamide (CTX) was used to generate a mouse model of premature ovarian failure. The results showed that Fer-1 treatment significantly restored the inhibitory effect of CTX on GPX4 expression in the cumulus cells and partially reversed the adverse effects of CTX on the follicular reserve in the ovaries, the number of oocytes retrieved, and the quality of the oocytes in mice. The study findings suggest that ferroptosis is involved in regulating ovarian aging and that GPX4 is a key gene in regulating ovarian follicle development and ferroptosis and a potential key target for treating ovarian aging.

Background: COPD is a heterogenous disease of the respiratory tract caused by diverse genetic factors along with environmental and lifestyle-related effects such as industrial dust inhalation and, most frequently, cigarette smoking. These factors lead to airflow obstruction and chronic respiratory symptoms. Additionally, the increased risk of infections exacerbates airway inflammation in COPD patients. As a consequence of the complex pathomechanisms and difficulty in treatment, COPD is among the leading causes of mortality both in the western countries and in the developing world. Results: The management of COPD is still a challenge for the clinicians; however, alternative interventions such as smoking cessation and lifestyle changes from a sedentary life to moderate physical activity with special attention to the diet may ameliorate patients' health. Here, we reviewed the effects of different dietary components and supplements on the conditions of COPD. Conclusions: COPD patients are continuously exposed to heavy metals, which are commonly present in cigarette smoke and polluted air. Meanwhile, they often experience significant nutrient deficiencies, which affect the detoxification of these toxic metals. This in turn can further disrupt nutritional balance by interfering with the absorption, metabolism, and utilization of essential micronutrients. Therefore, awareness and deliberate efforts should be made to check levels of micronutrients, with special attention to ensuring adequate levels of antioxidants, vitamin D, vitamin K2, magnesium, and iron, as these may be particularly important in reducing the risk of COPD development and limiting disease severity.

Flavonoids are a class of important polyphenolic compounds, renowned for their antioxidant properties. However, recent studies have uncovered an additional function of these natural flavonoids: their ability to inhibit ferroptosis. Ferroptosis is a key mechanism driving cell death in central nervous system (CNS) diseases, including both acute injuries and chronic neurodegenerative disorders, characterized by iron overload-induced lipid peroxidation and dysfunction of the antioxidant defense system. This review discusses the therapeutic potential of natural flavonoids from herbs and nutraceuticals as ferroptosis inhibitors in CNS diseases, focusing on their molecular mechanisms, summarizing findings from preclinical animal models, and providing insights for clinical translation. We specifically highlight natural flavonoids such as Baicalin, Baicalein, Chrysin, Vitexin, Galangin, Quercetin, Isoquercetin, Eriodictyol, Proanthocyanidin, (-)-epigallocatechin-3-gallate, Dihydromyricetin, Soybean Isoflavones, Calycosin, Icariside II, and Safflower Yellow, which have shown promising results in animal models of acute CNS injuries, including ischemic stroke, cerebral ischemia-reperfusion injury, intracerebral hemorrhage, subarachnoid hemorrhage, traumatic brain injury, and spinal cord injury. Among these, Baicalin and its precursor Baicalein stand out due to extensive research and favorable outcomes in acute injury models. Mechanistically, these flavonoids not only regulate the Nrf2/ARE pathway and activate GPX4/GSH-related antioxidant pathways but also modulate iron metabolism proteins, thereby alleviating iron overload and inhibiting ferroptosis. While flavonoids show promise as ferroptosis inhibitors for CNS diseases, especially in acute injury settings, further studies are needed to evaluate their efficacy, safety, pharmacokinetics, and blood-brain barrier penetration for clinical application.

As a new type of programmed cell death, ferroptosis is characterized by iron metabolism disorder and reactive oxygen species (ROS) accumulation, and is involved in regulating the occurrence and development of cancer cells. Especially in the field of liver cancer treatment, ferroptosis shows great potential because it can induce tumor cell death. Ubiquitination is a process of protein post-translational modification, which can affect the stability of proteins and regulate the progress of ferroptosis. This article reviews the research progress of ubiquitination modification of molecules related to ferroptosis pathway in the regulation of liver cancer, providing a new strategy for the treatment of liver cancer.

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in people over the age of 55. AMD currently affects approximately 8% of the world's population, and the number is growing as the global population ages. Growing evidence suggests that pathological choroidal neovascularization (CNV) is often related to more severe and rapid vision loss and blindness associated with AMD. The typical clinical treatment is intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents. However, some patients do not respond well to this therapy, and the potential risks of long-term repeated injections cannot be ignored. Therefore, there is an urgent need to explore the specific mechanisms of CNV development and find new, safe, and effective treatments. In this study, our data indicate that ferroptotic damage of retinal pigment epithelium (RPE) and its induced VEGFA overexpression are critical promoting factors in the development of CNV. Vitamin K can mediate the protection of RPE cells from ferroptotic damage and regulate the expression of eIF2α-ATF4-VEGFA in a VKOR/FSP1-dependent manner, inhibiting new angiogenesis to alleviate CNV. On the contrary, vitamin K antagonists (VKA) represented by warfarin, can promote RPE ferroptotic damage and related vascular proliferation in mice and eventually aggravate CNV lesions. However, vitamin K still showed significant protective effects even in the presence of VKA. Due to its significant anti-ferroptosis and anti-neovascular effects, as well as its relative safety and convenience of use, vitamin K has excellent potential in the treatment of CNV and is expected to become a clinically effective and safe new CNV treatment strategy.