The issue of light pollution has garnered increased attention recently, largely due to the widespread use of electronic devices. Blue light (BL) holds the highest energy level among visible light and has been extensively researched for its potential to cause damage to the retina. Ferroptosis, a recently identified form of programmed cell death form, has been linked to retinal diseases. However, the connection between BL-induced retinal damage and ferroptosis remains elusive. This study aims to investigate the involvement of ferroptosis in retinal damage under BL exposure and its underlying mechanism. In this study, a mouse retinal damage model and cultured ARPE-19 cells exposed to BL were employed. Various techniques including Haematoxylin-eosin staining, fundus photography, immunostaining, and transmission electron microscopy were employed to examine retinal structure and morphology changes resulting from BL exposure. To identify ferroptosis levels in vitro, we employed DCFH-DA, C11-BODIPY 581/591, and FeRhoNox™-1 probes. Additionally, real-time PCR and western blotting techniques were used to uncover potential targets in BL-induced ferroptosis. Our study showed that BL exposure can result in iron overload, oxidative stress, evidenced by increased markers TFR1, ACSL4, HO-1 and decreased expression level of SOD2, CAT and ferroptosis-associated gene of GPX4. Interestingly, we found that Deferoxamine mesylate, a compound capable of chelating excess Fe2+ caused by BL, effectively mitigated lipid peroxidation, and alleviated retinal damage both in vivo and in vitro. The discoveries will advance our knowledge of BL-induced retinal damage.

Iron-induced lipid peroxidation of phosphatidylethanolamine (PE) species is a key driver of ferroptosis in retinal pigment epithelial (RPE) cells, a process closely associated with age-related macular degeneration (AMD). The previous studies have demonstrated that induced retinal pigment epithelial (iRPE) cells generated by transcription factor-mediated reprogramming exhibit superior therapeutic efficacy in treating AMD. In this study, it is found that these iRPE cells are resistant to ferroptosis and further identified phosphoethanolamine/phosphocholine phosphatase 1 (PHOSPHO1) as a critical regulator underlying ferroptosis resistance. Mechanistically, PHOSPHO1 inhibits ferroptosis through two distinct mechanisms. First, it reduces PE levels in the endoplasmic reticulum, thereby limiting PE-derived lipid peroxidation. Second, it suppresses autophagy and ferritinophagy, leading to a reduction in intracellular free iron accumulation. Experiments using an in vivo rat model confirm that PHOSPHO1 effectively protects RPE cells from ferroptotic damage. These findings highlight PHOSPHO1 as a potential therapeutic target for AMD, providing insights into novel ferroptosis-based intervention strategies.

Heat stress (HS) is a significant health concern that adversely affects both human and animal health, particularly impacting liver function due to its central metabolic role. This study investigated the mechanisms underlying HS-induced liver injury, focusing on the role of ferroptosis, an iron-dependent form of cell death characterized by lipid peroxidation and cellular iron accumulation. Using mouse and cellular HS models, the results demonstrated that HS induced liver injury through ferroptosis, as evidenced by increased levels of malondialdehyde (MDA), oxidized glutathione (GSSG), and iron, alongside decreased glutathione (GSH) and glutathione peroxidase 4 (GPX4) expression. The ferroptosis inhibitor Ferrostatin-1 (Fer-1) effectively mitigated HS-induced liver damage, reducing oxidative stress and restoring GPX4 levels. Furthermore, HS promoted the lysosomal degradation of GPX4 via the chaperone-mediated autophagy (CMA) pathway, which was regulated by heat shock cognate protein 70 (HSC70) and lysosome-associated membrane protein 2A (LAMP2A). Knockdown of LAMP2A in hepatocytes significantly suppressed HS-induced GPX4 degradation, confirming the critical role of CMA in this process. Inhibition of CMA using Apoptozole, an HSC70 inhibitor, or Bafilomycin A1 (Baf-A1), a lysosomal inhibitor, further attenuated HS-induced ferroptosis and liver injury. These findings highlight the critical role of CMA-mediated GPX4 degradation in HS-induced ferroptosis and liver injury, providing potential therapeutic targets for mitigating HS-related liver damage.

Diabetic cardiomyopathy (DCM) is a common and fatal cardiac complication caused by diabetes, with its pathogenesis involving various forms of cell death and mitochondrial dysfunction, particularly ferroptosis and mitochondrial injury. Recent studies have indicated that ferroptosis and mitochondrial damage play crucial roles in the onset and progression of DCM, though their precise regulatory mechanisms remain unclear. Of particular interest is the interaction between ferroptosis and mitochondrial damage, as well as their synergistic effects, which are not fully understood. This review summarizes the roles of ferroptosis and mitochondrial injury in the progression of DCM and explores the molecular mechanisms involved, with an emphasis on the interplay between these two processes. Additionally, the article offers an overview of targeted drugs shown to be effective in cellular experiments, animal models, and clinical trials, analyzing their mechanisms of action and potential side effects. The goal is to provide insights for future drug development and clinical applications. Moreover, the review explores the challenges and prospects of multi-target combination therapies and personalized medicine interventions in clinical practice to offer strategic guidance for the comprehensive prevention and management of DCM.

Diabetic retinopathy (DR) represents the main ocular complication of diabetes. Targeting ferroptosis is a promising treatment of choice for various diabetic complications. N6-methyladenosine (m6A) demethylase alkylation repair homolog protein 5 (ALKBH5) functions as a pivotal regulator of ferroptosis, and we investigated its role and molecular mechanisms in ferroptosis in DR.

A DR mouse model was developed by streptozotocin (STZ) intraperitoneal injection. High glucose (HG)-induced human retinal pigment epithelial cells (ARPE-19) were used as a DR model in vitro. ALKBH5, YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) and acyl-CoA synthetase long-chain family member 4 (ACSL4) expression levels were examined by RT-qPCR and Western blot. The biological functions of ALKBH5 in vitro and in vivo were investigated by gain-of-function and loss-of-function analyses. ALKBH5's downstream regulatory mechanisms were detected by bioinformatics analysis, RNA pull-down, MeRIP-qPCR and actinomycin D assay.

ALKBH5 was under-expressed while YTHDF1 and ACSL4 were up-regulated in the retinal tissues of STZ-induced DR mice and HG-stimulated ARPE-19 cells. Ectopically expressed ALKBH5 or YTHDF1 knockdown partially reversed the increased ferroptosis in vitro and in vivo, evidenced by decreased levels of Fe2+, malondialdehyde and reactive oxygen species yet increased glutathione level. ALKBH5 mediated m6A modification of ACSL4 mRNA and disrupted its stability in a YTHDF1-dependent manner. Importantly, in vivo data demonstrated that overexpression of ALKBH5 or YTHDF1 knockdown repressed ferroptosis and alleviated DR by down-regulating ACSL4.

These findings suggest that ALKBH5 may delay DR progression by reducing ferroptosis through the m6A-YTHDF1-ACSL4 axis, offering therapeutic paradigms for the treatment of DR.

Sodium fluoride-induced ocular damage constitutes a significant public health concern globally; however, the precise molecular mechanisms underlying this issue remain obscure. This study aims to investigate the effects of sodium fluoride on myopia and to offer novel theoretical foundations for future strategies in myopia prevention and control. The experimental data showed that sodium fluoride could promote myopia progression, and through bioinformatics analysis, we found that sodium fluoride could affect the ferroptosis pathway. Western blotting and redox kit assays further confirmed that sodium fluoride activates the ferroptosis pathway. We also demonstrated that PIEZO1 plays a crucial role in sodium fluoride-induced myopia, and that the PIEZO1 inhibitor (GsMTx4) can inhibit the ferroptosis pathway. Subsequently, we identified PIEZO1 as a potential target of baicalin, which inhibited PIEZO1 expression in vivo and in vitro, as confirmed by molecular docking modeling and CETSA assays. Finally, we found that baicalin inhibited sodium fluoride-induced myopia via PIEZO1. Taken together, our findings indicate that sodium fluoride can promote myopia progression by activating the ferroptosis pathway through PIEZO1, and that targeting PIEZO1 expression can delay myopia progression, which may provide a new drug target for myopia treatment in the future.

Diabetic cataract (DC) is an ocular complication caused by diabetes. Currently, the main treatments for DC include pharmacological therapy and surgical intervention. The core objective of this study is to elucidate the specific mechanism of action of emodin in the treatment of DC, thereby providing potential targets for the treatment of DC.

CCK-8 kit was used to detect the effect of emodin on the activity of lens epithelial cells (LECs). The impact of emodin on the expression of inflammatory factors and apoptosis in high glucose-induced LECs were evaluated by utilizing ELISA and flow cytometry. Then, commercial kits were performed to detect the regulatory effects of emodin on oxidative stress and ferroptosis in high glucose LECs. The potential mechanism of emodin in combating DC by inhibiting ferroptosis was analyzed by network pharmacology methods, and protein binding activity to emodin was measured by molecular docking. Besides, western blot (WB) assay was used to detect the effect of emodin on p53.

Firstly, the results of CCK-8 showed that emodin could effectively alleviate the decrease of LECs cell activity and Lactate dehydrogenase (LDH) release induced by high glucose. Emodin suppressed high glucose-induced apoptosis of LECs, reduced the release of inflammatory factors, and alleviated oxidative stress and ferroptosis. GO and KEGG analyses confirmed the involvement of oxidative stress (OS), inflammatory response, and ferroptosis in the process of emodin treatment for DC. Molecular docking studies showed that emodin stably bound to proteins such as TP53, TNF, IL-6, and IL-1β. Additionally, WB results indicated that emodin alleviated high glucose-induced ferroptosis by binding to p53.

Collectively, these data suggest that emodin alleviates damage to LECs by interfering with the p53-mediated ferroptosis pathway, thereby attenuating DC disease, which offered new directions for the development of new drugs.

Diabetic retinopathy (DR) is a leading cause of blindness globally. Buyang Huanwu decoction (BHD) is a traditional Chinese medicine for treating DR, but its therapeutic mechanisms are not fully understood. This study aimed to elucidate and validate the underlying mechanisms of BHD in DR treatment through network pharmacology and in vitro experiments. We identified active compounds in BHD and their associated targets using the TCMSP and SwissTargetPrediction. DR-related targets were sourced from GeneCards, NCBI, and OMIM databases. The protein-protein interaction (PPI) network and enrichment analyses were employed to predict common targets and pathways. Subsequent molecular docking and in vitro experiments, including cell viability assays, RT-qPCR, flow cytometry, and Western blot, were conducted to validate the anti-DR mechanism of BHD. Network pharmacology identified paeoniflorin as a key active compound in BHD for treating DR, with VEGFA emerging as a central target. Molecular docking suggested a strong binding affinity between paeoniflorin and VEGFA. In vitro experiments confirmed that paeoniflorin attenuated high glucose-induced increases in cell viability, migration, apoptosis, and inflammatory cytokine expression in retinal pigment epithelial cells. The therapeutic effect of paeoniflorin was primarily mediated through the downregulation of VEGFA expression. Our study demonstrates that paeoniflorin, a key active compound in BHD, effectively mitigates DR by downregulating VEGFA expression and reducing high glucose-induced cellular alterations, thereby highlighting its potential as a therapeutic agent for DR.

Stroke, as a neurological disorder with a poor overall prognosis, has long plagued the patients. Current stroke therapy lacks effective treatments. Ferroptosis has emerged as a prominent subject of discourse across various maladies in recent years. As an emerging therapeutic target, notwithstanding its initial identification in tumor cells associated with brain diseases, it has lately been recognized as a pivotal factor in the pathological progression of stroke. Acyl-CoA synthetase long-chain family member 4 (ACSL4) is a potential target and biomarker of catalytic unsaturated fatty acids mediating ferroptosis in stroke. Specifically, the upregulation of ACSL4 leads to heightened accumulation of lipid peroxidation products and reactive oxygen species (ROS), thereby exacerbating the progression of ferroptosis in neuronal cells. ACSL4 is present in various tissues and involved in multiple pathways of ferroptosis. At present, the pharmacological mechanisms of targeting ACSL4 to inhibit ferroptosis have been found in many drugs, but the molecular mechanisms of targeting ACSL4 are still in the exploratory stage. This paper introduces the physiopathological mechanism of ACSL4 and the current status of the research involved in ferroptosis crosstalk and epigenetics, and summarizes the application status of ACSL4 in modern pharmacology research, and discusses the potential application value of ACSL4 in the field of stroke.

Diabetes retinopathy (DR) represents a microvascular disease in diabetes. Growth arrest-specific 1 (GAS1) is differentially expressed in rat retinal Müller cells under high glucose (HG) conditions, and its promotion of ferroptosis contributes to retinal cell death. However, the influence of GAS1 in DR is elusive. Herein, we aimed to investigate the effect and potential mechanism based on GAS1-mediated ferroptosis on DR.

After HG treatment, the differentially expressed genes in rat retinal Müller cells were analyzed by transcriptome sequencing followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses; finally, GAS1 was selected. The effects of GAS1 knockdown/overexpression and nuclear factor erythroid 2-related factor (Nrf2) silencing on viability, apoptosis, lipid peroxidation, Fe2+, and oxidative stress levels in HG-induced/transfected Müller cells were measured by Cell Counting Kit-8 (CCK-8) assay, flow cytometry, and commercial reagent kits. The potential effects of GAS1 and Nrf2, especially on GAS1, Nrf2, and Kelch-like ECH-associated protein 1 (Keap1) expressions in cells, were determined by quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot.

HG treatment decreased cell viability and glutathione (GSH) levels and increased apoptosis, lipid reactive oxygen species (ROS), glutathione disulfide (GSSG), malondialdehyde (MDA), oxidative stress, and Fe2+ levels in Müller cells (p < 0.01). HG treatment also upregulated GAS1, Keap1, and total Nrf2 expressions while downregulating nuclear Nrf2 in Müller cells (p < 0.001). GAS1 downregulation enhanced cell viability, GSH levels, and nuclear Nrf2 expression while reducing the levels of apoptosis, lipid ROS, GSSG, MDA, Fe2+, Keap1, and total Nrf2 in HG-treated Müller cells (p < 0.001), whereas GAS1 overexpression had the opposite effects. Additionally, Nrf2 silencing reversed the impact of GAS1 overexpression in HG-treated Müller cells (p < 0.05).

GAS1 inhibits Keap1/Nrf2 signaling transduction in activating ferroptosis in retinal Müller cells; thus, this study can aid in setting the stage for novel treatment methods against DR.

Diabetic retinopathy (DR) is a common microvascular complication of diabetes and a leading cause of vision loss worldwide. Although several mechanisms have been implicated in the pathogenesis of DR, emerging evidence suggests a link between ferroptosis and DR. Unfortunately, the exact mechanism underlying this connection is not clear. Therefore, investigating the role of ferroptosis in diabetic retinopathy holds promise for advancing our understanding of this complex disease and developing innovative treatments. We have identified differentially expressed genes (DEGs) and differentially expressed marker genes (DEMGs) from open-source single-cell RNA sequencing datasets by using in depth in silico approach. Subsequently, ferroptosis-associated DEGs (FA-DEGs), ferroptosis-associated DEMGs (FA-DEMGs), and ferroptosis-associated Hub Genes (FAHGs) were identified. The FDA-approved drugs for our target proteins were also identified, and their ADMET properties were assessed. Molecular docking and simulation were utilized to explore the interaction stability of the compounds with the target proteins. Overall, we identified 63 FA-DEMGs that were significantly enriched in Peroxiredoxin activity, Ferroptosis, Mitophagy, and Autophagy. Further analysis predicted that PRDX1 and UBC are candidate target proteins. Molecular docking results showed that dexamethasone has a high binding affinity for both PRDX1 and UBC. Additionally, molecular dynamics simulations revealed that dexamethasone (which showed the best hit in the docking analysis) exhibited a 'stable effect' on both PRDX1 and UBC. To summarize, this study showed that PRDX1 and UBC could be suitable therapeutic targets for dexamethasone, which might be helpful in the advance of DR treatments in the future.

Dysfunction of keratinocytes affects diabetic wound healing, but underlying mechanisms have not been understood. This study examines crotonylation's role in ferroptosis and autophagy in keratinocytes, particularly regarding ACSL4, using STZ-induced diabetic rats and high glucose-exposed keratinocytes to assess these processes. The ACSL4 knockdown was achieved using adenovirus in wounds to examine the impact of ferroptosis modulation on healing diabetic wounds. MB-3 was utilized to block the H3K27 crotonylation (H3K27cr) in order to clarify the regulatory function of crotonylation in both autophagy and ferroptosis. In STZ-induced diabetic skin and high glucose-exposed keratinocytes, ferroptosis mediated by ACSL4 and suppression of autophagic flux were demonstrated. Moreover, the downregulation of ACSL4 triggered ferroptosis in adjacent wounds of diabetic rats and improved wound healing. The degradation of ACSL4 may be observed via the autophagy-lysosome pathway in keratinocytes. Downregulation of SQSTM1 in diabetic keratinocytes leads to autophagy inhibition and modulates the protein level of ACSL4. Mechanistically, total crotonylation levels and H3K27cr were remarkably elevated in the skin and keratinocytes of diabetic rats; blocking high glucose-induced H3K27cr with MB-3 can enhance SQSTM1 transcription and expression while promoting autophagy and reducing ACSL4-induced ferroptosis in keratinocytes. Therefore, H3K27cr influences autophagy by adjusting SQSTM1 to facilitate ACSL4-triggered ferroptosis in diabetic keratinocytes. This study clarifies the relationships between acylation modifications, autophagy, and ferroptosis, while also offering mechanistic insights and potential therapeutic targets for issues associated with diabetic wound healing.

Background: Diabetic retinopathy (DR) is a microangiopathy resulting from diabetes mellitus. Studies on vitreous samples have shed insights into the etiology of DR and highlighted the role of molecular targets in DR treatment. The present study probed into the role of extracellular matrix metalloproteinase inducer (EMMPRIN) in DR by examining its influence on inflammation, angiogenesis, matrix metalloproteinases (MMPs), and blood-retina barrier injury.Methods: After the induction of diabetes in rats through streptozotocin injection, SP-8356 (an inhibitor for EMMPRIN) was administered to rats for silencing EMMPRIN in vivo. Serum and vitreous EMMPRIN levels were assessed by ELISA and western blotting. The concentration and mRNA expression of proinflammatory cytokines in rat vitreous samples were quantified through ELISA or RT-qPCR. Western blotting or RT-qPCR was performed to measure protein or mRNA levels of MMPs, tight junction factors, and angiogenic factors.Results: High EMMPRIN levels were found in both serum and vitreous samples of DR rats. Inhibition of EMMPRIN using SP-8356 ameliorated DR-induced high levels of inflammatory cytokines, MMPs, and angiogenic factors and rescued DR-induced low expression levels of tight junction factors in rat vitreous samples.Conclusions: EMMPRIN accelerates inflammation, angiogenesis and blood-retina barrier injury in DR by regulating MMPs.

Autophagy refers to the proteolytic degradation of cytoplasmic components by lysosomes, and includes three defined types: macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy. Although the regulatory pathways of macroautophagy are well defined, how CMA is accurately regulated remains less understood. In recent years, emerging evidence has suggested that chaperone-mediated autophagy is regulated by multiple mechanisms at nucleic acid and protein levels. In this review, we summarized recent progress on multiple regulatory mechanisms and functions concerning CMA, as well as novel treatments targeting specific regulation sites.

Chaperone mediated autophagy (CMA) represents a specialized mechanism of lysosomal protein breakdown, playing a crucial role as a metabolic pathway that helps to regulate and sustain cellular and systemic physiological equilibrium. Within the CMA process, proteins that contain sequences similar to KFERQ are specifically identified by the heat shock cognate protein 70. These proteins are then chaperoned to the lysosomes for subsequent degradation, a process facilitated by the lysosome associated membrane protein 2A. This particular research employed bioinformatics techniques to systematically screen for potential substrates of CMA. ApoE has a KFERQ like motif, which may be a substrate for CMA. Under conditions of starvation, hypoxia, H2O2, PA, and NaIO3, the expression of the rate limiting factor LAMP2A in CMA and ApoE increased significantly (P < 0.05). Under conditions of NaIO3, the expression of CMA related gene mRNA increased significantly (P < 0.05). When we use lysosomal blocker CQ to inhibit CMA activity, the expression level of ApoE in retinal pigment epithelial cells increased, and the difference was statistically significant (P < 0.05). When we inhibit CMA, the accumulation of ApoE in retinal pigment epithelial cells increases and cell viability decreases. When we activate CMA, the accumulation of ApoE decreases and cell viability increases. In retinal pigment epithelial cells, the drusen associated protein ApoE can be degraded through the CMA pathway.

Evidence suggests that the progression of acute kidney injury (AKI) is driven by tubular epithelial cell (TEC) injury. However, the role of ferroptosis during the regulatory process remains unclear. Fifty-three patients with AKI were included to examine the expressions of Rab7, glutathione peroxidase 4 (GPX4), and Hif-1α by immunohistochemistry. The relationship between these expressions and serum creatinine (Scr) and blood urea nitrogen (BUN) levels was analyzed. After inducing AKI and ferroptosis through bilateral renal artery ischemia-reperfusion injury (I/R) in vivo and hypoxia in vitro, we examined the expression of Rab7. The injury and ferroptosis were observed following the administration of erastin or ferrostatin-1 (Fer-1), as well as the downregulation of Rab7. In addition, we investigated the degradation of GPX4 and chaperone-mediated autophagy (CMA). Finally, we assessed the injury and ferroptosis after the combination of RAS-selective lethal 3 (RSL3) and downregulation of Rab7. GPX4 exhibited an inverse correlation with Hif-1α, Scr, BUN, and Rab7. Conversely, Rab7 was positively correlated with Scr and BUN. Both in vivo and in vitro models resulted in elevated levels of ferroptosis and Rab7. Erastin exacerbated ferroptosis and injury, but this effect was mitigated by Fer-1. Downregulation of Rab7 reversed the increased ferroptosis and injury. Hypoxia enhanced lysosomal transport and degradation of GPX4 through activation of CMA. Furthermore, the reversal of these effects was observed upon the downregulation of Rab7. However, the results obtained from Rab7 downregulation were subsequently reversed by RSL3. Ferroptosis is important in TEC injury during AKI and Rab7 promotes tubular ferroptosis by facilitating CMA-mediated degradation of GPX4.NEW & NOTEWORTHY To explore the mechanism underlying ferroptosis in I/R-induced renal injury and to confirm the effect of Rab7, we first evaluated ferroptosis in renal biopsy samples, and then examined Rab7 expression and renal tubular injury during AKI in vivo and in vitro. Finally, we performed in vitro experiments to investigate the specific role of Rab7 in the regulation of ferroptosis and showed that the regulatory mechanism was related to CMA-mediated GPX4 degradation in renal TECs.

Drug resistance is a common challenge in clinical tumor treatment. A reduction in drug sensitivity of tumor cells is often accompanied by an increase in autophagy levels, leading to autophagy-related resistance. The effectiveness of combining chemotherapy drugs with autophagy inducers/inhibitors has been widely confirmed, but the mechanisms are still unclear. Ferroptosis and pyroptosis can be affected by various types of autophagy. Therefore, ferroptosis and pyroptosis have crosstalk via autophagy, potentially leading to a switch in cell death types under certain conditions. As two forms of inflammatory programmed cell death, ferroptosis and pyroptosis have different effects on inflammation, and the cGAS-STING signaling pathway is also involved. Therefore, it also plays an important role in the progression of some chronic inflammatory diseases. This review discusses the relationship between autophagy, ferroptosis and pyroptosis, and attempts to uncover the reasons behind the evasion of tumor cell death and the nature of drug resistance.

The increasing prevalence of LED technology heightened blue light (BL) exposure, raising concerns about its long-term effects on ocular health. This study investigated the transcriptomic response of conjunctiva to BL exposure, highlighting potential biomarkers for conjunctival injury. We exposed human conjunctival epithelial cells and C57BL/6 mice to BL to establish in vitro and in vivo models and identified the responsive genes in mice's conjunctiva to BL exposure by RNA sequencing transcriptome analysis. Western blotting, wound healing assays, transwell assay, and phalloidin staining assessed phenotypes of epithelial-mesenchymal transition (EMT). BL disrupted cell conjunction and regulated EMT-related proteins. RNA sequencing analysis revealed upregulation of ITGB4 and enrichment of cell migration and adhesion pathways. Reactive oxygen species-mediated damage caused by BL upregulated ITGB4 expression, promoting cell migration and EMT through the extracellular signal-regulated kinase /Snail pathway.

Recent studies demonstrate that lipid peroxidation-induced ferroptosis participates in 2,2',4,4'-tetrabromodiphenyl ether (BDE-47)-evoked neurotoxicity and cognitive dysfunction. Melatonin has been indicated to confer neuroprotection against brain diseases via its potent anti-ferroptotic effects. Therefore, this study aims to explore whether melatonin can mitigate BDE-47-elicited cognitive impairment via suppressing ferroptosis, and further delineate the underlying mechanisms. Our results found that melatonin administration effectively inhibited BDE-47-induced ferroptosis in mice hippocampi and murine hippocampal neuronal HT-22 cells. Acyl-CoA synthetase long-chain family member 4 (ACSL4), a key lipid metabolism enzyme dictating ferroptosis sensitivity, accompanied by higher MDA and lipid reactive oxygen species (ROS), was remarkably increased under BDE-47 stress, while melatonin supplementation could suppress the elevated ACSL4 in vivo and in vitro. Furthermore, melatonin facilitated lysosomal ACSL4 degradation through enhancing lysosome-associated membrane protein type 2a (LAMP2a) expression and chaperone-mediated autophagy (CMA) activity, while LAMP2a knockdown abrogated the positive effects of melatonin on ACSL4 elimination in BDE-47-treated HT-22 cells. Moreover, nuclear factor erythroid 2-related factor 2 (Nrf2) activation by melatonin contributed to LAMP2a upregulation and CMA of ACSL4 and subsequent neuronal ferroptosis. Importantly, melatonin, CMA activator CA77.1, and ACSL4 inhibitor rosiglitazone (RSG) administration substantially attenuated neuronal/synaptic injury and cognitive deficits following BDE-47 exposure. Taken together, these findings revealed that melatonin could prevent BDE-47-provoked ferroptosis in the hippocampal neurons and mitigate cognitive dysfunction by facilitating ACSL4 degradation via Nrf2-chaperone-mediated autophagy. Therefore, melatonin might be a potential candidate for treating BDE-47-elicited neurotoxicity and neurobehavioral disorder.

The detachment of the retinal neuroepithelium from the retinal pigment epithelium (RPE), often due to a retinal tear and subsequent subretinal fluid (SRF) accumulation, is a critical factor leading to photoreceptor cells (PR) death and permanent vision impairment in retinal detachment (RD) scenarios. Predicting postoperative visual recovery is challenging, even with surgical reattachment. Research has indicated that increased iron and transferrin (TF) saturation in the vitreous fluid (VF) correlates with poorer visual outcomes, suggesting a potential role for ferroptosis, a form of regulated cell death, in PR following RD. To explore this hypothesis, we analyzed the VF of RD patients for ferroptosis markers, revealing reduced levels of glutathione peroxidase 4 (GPX4), glutathione (GSH), and reduced nicotinamide adenine dinucleotide phosphate (NADPH), alongside elevated levels of Long-chain acyl-CoA synthetase 4(ACSL4), malondialdehyde (MDA), and ferrous iron. We then developed a mouse model to simulate RD and administered the iron chelator deferiprone (DFP) as a treatment. Our findings indicated that DFP mitigated ferroptosis in the retina, thereby preserving retinal architecture and function. Collectively, our study establishes the occurrence of ferroptosis in RD and demonstrates the therapeutic potential of DFP in protecting PR and treating RD.

Ferroptosis is a type of iron-dependent cell death that differs from apoptosis, necroptosis, autophagy, and other forms of cell death. It is mainly characterized by the accumulation of intracellular lipid peroxides, redox imbalance, and reduced levels of glutathione and glutathione peroxidase 4. Studies have demonstrated that ferroptosis plays an important regulatory role in the occurrence and development of neurodegenerative diseases, stroke, traumatic brain injury, and ischemia-reperfusion injuries. Multiple mechanisms, such as iron metabolism, ferritinophagy, p53, and p62/Keap1/Nrf2, as well as the combination of FSP1/CoQ/NADPH and hepcidin/FPN-1 can alter the vulnerability to ferroptosis. Nevertheless, there has been limited research on the development and management of ferroptosis in the realm of eye disorders, with most studies focusing on retinal conditions such as age-related macular degeneration and retinitis pigmentosa. This review offers a thorough examination of the disruption of iron homeostasis in eye disorders, investigating the underlying mechanisms. We anticipate that the occurrence of ferroptotic cell death will not only establish a fresh field of study in eye diseases, but also present a promising therapeutic target for treating these diseases.

The pathophysiology of cardiovascular disease (CVD) is complex and presents a serious threat to human health. Cardiomyocyte loss serves a pivotal role in both the onset and progression of CVD. Among various forms of programmed cell death, ferroptosis, along with apoptosis, autophagy and pyroptosis, is closely linked to the advancement of CVD. Ferroptosis, a mechanism of cell death, is driven by the buildup of oxidized lipids and excess iron. This pathway is modulated by lipid, amino acid and iron metabolism. Key characteristics of ferroptosis include disrupted iron homeostasis, increased peroxidation of polyunsaturated fatty acids due to reactive oxygen species, decreased glutathione levels and inactivation of glutathione peroxidase 4. Treatments targeting ferroptosis could potentially prevent or alleviate CVD by inhibiting the ferroptosis pathway. Ferroptosis is integral to the pathogenesis of several types of CVD and inhibiting its occurrence in cardiomyocytes could be a promising therapeutic strategy for the future treatment of CVD. The present review provided an in‑depth analysis of advancements in understanding the mechanisms underlying ferroptosis. The present manuscript summarized the interplay between ferroptosis and CVDs, highlighting its dual roles in these conditions. Additionally, potential therapeutic targets within the ferroptosis pathway were discussed, alongside the current limitations and future directions of these novel treatment strategies. The present review may offer novel insights into preventive and therapeutic approaches for CVDs.

Cells rely on autophagy for the degradation and recycling of damaged proteins and organelles. Chaperone-mediated autophagy (CMA) is a selective process targeting proteins for degradation through the coordinated function of molecular chaperones and the lysosome‑associated membrane protein‑2A receptor (LAMP2A), pivotal in various cellular processes from signal transduction to the modulation of cellular responses under stress. In the present review, the intricate regulatory mechanisms of CMA were elucidated through multiple signaling pathways such as retinoic acid receptor (RAR)α, AMP‑activated protein kinase (AMPK), p38‑TEEB‑NLRP3, calcium signaling‑NFAT and PI3K/AKT, thereby expanding the current understanding of CMA regulation. A comprehensive exploration of CMA's versatile roles in cellular physiology were further provided, including its involvement in maintaining protein homeostasis, regulating ferroptosis, modulating metabolic diversity and influencing cell cycle and proliferation. Additionally, the impact of CMA on disease progression and therapeutic outcomes were highlighted, encompassing neurodegenerative disorders, cancer and various organ‑specific diseases. Therapeutic strategies targeting CMA, such as drug development and gene therapy were also proposed, providing valuable directions for future clinical research. By integrating recent research findings, the present review aimed to enhance the current understanding of cellular homeostasis processes and emphasize the potential of targeting CMA in therapeutic strategies for diseases marked by CMA dysfunction.

Background: Diabetic liver injury is a serious complication due to the lack of effective treatments and the unclear pathogenesis. Ferroptosis, a form of cell death involving reactive oxygen species (ROS)-dependent lipid peroxidation (LPO), is closely linked to autophagy and diabetic complications. Therefore, this study is aimed at investigating the role of autophagy in regulating ferroptosis by modulating the degradation of acyl-CoA synthetase long-chain family member 4 (ACSL4) in diabetic hepatocytes and its potential impact on diabetic liver injury. Methods: Initially, ferroptosis and autophagy were assessed in liver tissues from streptozotocin-induced diabetic rats and in palmitic acid (PA)-treated LO2 cells. Subsequently, the study focused on elucidating the regulatory role of autophagy in mediating ferroptosis through the modulation of ACSL4 expression in PA-treated LO2 cells. Results: The results demonstrated that ACSL4-mediated ferroptosis and inhibition of autophagy were observed in diabetic hepatocytes in vivo and in PA-treated LO2 cells. Additionally, the ferroptosis inhibitor was able to mitigate the PA-induced cell death in LO2 cells. Mechanistically, the stability and expression level of the ACSL4 protein were upregulated and primarily degraded via the autophagy-lysosome pathway in PA-treated LO2 cells. The use of the autophagy inhibitor 3-methyladenine (3-MA) and the inducer rapamycin further demonstrated that autophagy regulated ferroptosis by mediating ACSL4 degradation, highlighting its critical role in diabetic liver injury. Conclusions: These results elucidate the roles of ferroptosis, autophagy, and their interactions in the pathogenesis of diabetic liver injury, offering potential therapeutic targets. Furthermore, they shed light on the pathogenesis of ferroptosis and other diabetic complications.

Diabetic retinopathy (DR), as one of the most common and significant microvascular complications of diabetes mellitus (DM), continues to elude effective targeted treatment for vision loss despite ongoing enrichment of the understanding of its pathogenic mechanisms from perspectives such as inflammation and oxidative stress. Recent studies have indicated that characteristic neuroglial degeneration induced by DM occurs before the onset of apparent microvascular lesions. In order to comprehensively grasp the early-stage pathological changes of DR, the retinal neurovascular unit (NVU) will become a crucial focal point for future research into the occurrence and progression of DR. Based on existing evidence, ferroptosis, a form of cell death regulated by processes like ferritinophagy and chaperone-mediated autophagy, mediates apoptosis in retinal NVU components, including pericytes and ganglion cells. Autophagy-dependent ferroptosis-related factors, including BECN1 and FABP4, may serve as both biomarkers for DR occurrence and development and potentially crucial targets for future effective DR treatments. The aforementioned findings present novel perspectives for comprehending the mechanisms underlying the early-stage pathological alterations in DR and open up innovative avenues for investigating supplementary therapeutic strategies.

This study investigated the involvement of discoidin domain receptor (DDR) in dry eye and assessed the potential of specific DDR inhibitors as a therapeutic strategy for dry eye by exploring the underlying mechanism.

Dry eye was induced in Wistar rats by applying 0.2% benzalkonium chloride (BAC), after which rats were treated topically for 7 days with DDR1-IN-1, a selective inhibitor of DDR1. Clinical manifestations of dry eye were assessed on Day-7 post-treatment. Histological evaluation of corneal damage was performed using haematoxylin and eosin (H&E) staining. In vitro, immortalized human corneal epithelial cells (HCECs) exposed to hyperosmotic stress (HS) were treated with varying doses of DDR1-IN-1 for 24 h. The levels of lipid peroxidation in dry eye corneas or HS-stimulated HCECs were assessed. Protein levels of DDR1/DDR2 and related pathways were detected by western blotting. The cellular distribution of acyl-CoA synthetase long chain family member 4 (ACSL4) and Yes-associated protein (YAP) was evaluated using immunohistochemistry or immunofluorescent staining.

In dry eye corneas, only DDR1 expression was significantly up-regulated compared with normal controls. DDR1-IN-1 treatment significantly alleviated dry eye symptoms in vivo. The treatment remarkably reduced lipid hydroperoxide (LPO) levels and suppressed the expression of ferroptosis markers, particularly ACSL4. Overexpression or reactivation of YAP diminished the protective effects of DDR1-IN-1, indicating the involvement of the Hippo/YAP pathway in DDR1-targeted therapeutic effects.

This study confirms the significance of DDR1 in dry eye and highlights the potential of selective DDR1 inhibitor(s) for dry eye treatment.

The liver damage caused by Diabetes Mellitus (DM) has attracted increasing attention in recent years. Liver injury in DM can be caused by ferroptosis, a form of cell death caused by iron overload. However, the role of iron transporters in this context is still not clear. Herein, we attempted to shed light on the pathophysiological mechanism of ferroptosis. DM was induced in 8-week-old male rats by streptozotocin (STZ) before assessment of the degree of liver injury. Together with histopathological changes, variations in glutathione peroxidase 4 (GPX4), glutathione (GSH), superoxide dismutase (SOD), transferrin receptor 1 (TFR1), ferritin heavy chain (FTH), ferritin light chain (FTL), ferroportin and Prussian blue staining, were monitored in rat livers before and after treatment with Fer-1. In the liver of STZ-treated rats, GSH and SOD levels decreased, whereas those of malondialdehyde (MDA) increased. Expression of TFR1, FTH and FTL increased whereas that of glutathione peroxidase 4 (GPX4) and ferroportin did not change significantly. Prussian blue staining showed that iron levels increased. Histopathology showed liver fibrosis and decreased glycogen content. Fer-1 treatment reduced iron and MDA levels but GSH and SOD levels were unchanged. Expression of FTH and FTL was reduced whereas that of ferroportin showed a mild decrease. Fer-1 treatment alleviated liver fibrosis, increased glycogen content and mildly improved liver function. Our study demonstrates that ferroptosis is involved in DM-induced liver injury. Regulating the levels of iron transporters may become a new therapeutic strategy in ferroptosis-induced liver injury.

Retinal ischemia‒reperfusion (IR) is a major contributor to vision impairment and irreversible vision loss due to retinal ganglion cell (RGC) injury or loss. Contemporary therapeutic approaches predominantly focus on the amelioration of symptoms rather than addressing the fundamental etiological factors. Oxidative stress is a notable feature and an important mediator of IR damage. Lycium barbarum polysaccharide (LBP), the main active ingredient of Lycium barbarum, has various pharmacological effects, including antioxidation, immunoregulation, and neuroprotective effects. In this study, the ROS-consumable moiety phenylboronic acid pinacol ester (PBA) is introduced to LBP molecules, which can self-assemble into nanoparticles in aqueous solution. This nanoparticle (termed PLBP) can reduce the cellular ROS levels and enhance the antioxidant capability of RGCs by activating the NRF2 pathway, thus protecting RGCs from ferroptosis and preserving visual function in response to IR injury. PLBP also reduces neuroinflammation by inhibiting the ability of microglia to phagocytose, migrate, secrete inflammatory cytokines, and activate the NF-κB pathway. In conclusion, this approach can be used as an inspiration for the future development of neuroprotective drugs.

Diabetic retinopathy (DR) is a prevalent complication of diabetes, with a rising global incidence, and can result in significant vision impairment and potential blindness in adults. Corilagin (COR) has been shown to regulate several pathological processes. However, the specific protective role and mechanism of action of COR in DR remain unknown.

The protective effects and mechanisms of COR in DR were examined using the ARPE-19 cell line and C57BL/6 mice. Intraretinal tissue damage and molecular markers were evaluated to investigate the impact of COR on oxidative stress and cell death pathways.

In vitro, COR significantly reduced the cytotoxic effects of high glucose (HG) on ARPE-19 cells. Furthermore, COR also effectively decreased HG-induced lipid peroxidation, iron deposition, and ferroptosis and reduced damage to retinal tight junction proteins. Similarly, an in vivo study of streptozotocin (STZ)-induced DM mice showed that the daily gavage of COR for eight weeks notably alleviated DR. Mechanistically, COR activated the Nrf2 antioxidant signaling pathway both in vivo and in vitro, preventing HG-induced alterations in morphological and biochemical parameters. Notably, our study demonstrated that compared with controls, Nrf2 knockout mice and siNrf2-treated cells were more vulnerable to ferroptosis under HG conditions, and the protective effect of COR on DR was substantially diminished in these models.

These data indicate that COR has a protective effect against HG-induced retinal injury via a mechanism associated with the Nrf2-dependent antioxidant pathway and ferroptosis regulation.

Macroautophagy/autophagy is an intracellular degradation pathway that has an important effect on both healthy and diseased pancreases. It protects the structure and function of the pancreas by maintaining organelle homeostasis and removing damaged organelles. A variety of pancreas-related diseases, such as diabetes, pancreatitis, and pancreatic cancer, are closely associated with autophagy. Genetic studies that address autophagy confirm this view. Loss of autophagy homeostasis (lack or overactivation) can lead to a series of adverse reactions, such as oxidative accumulation, increased inflammation, and cell death. There is growing evidence that stimulating or inhibiting autophagy is a potential therapeutic strategy for various pancreatic diseases. In this review, we discuss the multiple roles of autophagy in physiological and pathological conditions of the pancreas, including its role as a protective or pathogenic factor.

Ferroptosis, an iron-dependent form of regulated cell death, is emerging as a crucial regulator of human physiology and pathology. Increasing evidence showcases a reciprocal relationship between ferroptosis and dysregulated metabolism, propagating a pathogenic vicious cycle that exacerbates pathology and human diseases, particularly metabolic disorders. Consequently, there is a rapidly growing interest in developing ferroptosis-based therapeutics. Therefore, a comprehensive understanding of the intricate interplay between ferroptosis and metabolism could provide an invaluable resource for mechanistic insight and therapeutic development. In this review, we summarize the important metabolic substances and associated pathways in ferroptosis initiation and progression, outline the cascade responses of ferroptosis in disease development, overview the roles and mechanisms of ferroptosis in metabolic diseases, introduce the methods for ferroptosis detection, and discuss the therapeutic perspectives of ferroptosis, which collectively aim to illustrate a comprehensive view of ferroptosis in basic, translational, and clinical science.

Oxidative stress has been identified as a major contributor to the pathogenesis of DR, and many diagnostic and therapeutic strategies have been developed to target oxidative stress. Our aim was to understand the contribution of the country of origin of the publication, the institution, the authors, and the collaborative relationship between them.

We performed a bibliometric analysis to summarize and explore the research hotspots and trends of oxidative stress in the DR.

We observe an upward trend in the number of posts on related topics from year to year. Expanding on this, Queens University Belfast is the most influential research institution. Current research hotspots and trends focus on the mechanism of autophagy and NLRP3 inflammasome's role in oxidative stress in DR.

We conducted a multi-dimensional analysis of the research status of oxidative stress in diabetic retinopathy through bibliometric analysis, and proposed possible future research trends and hotspots.

Diabetes leads to a significantly accelerated incidence of various related macrovascular complications, including peripheral vascular disease and cardiovascular disease (the most common cause of mortality in diabetes), as well as microvascular complications such as kidney disease and retinopathy. Endothelial dysfunction is the main pathogenic event of diabetes-related vascular disease at the earliest stage of vascular injury. Understanding the molecular processes involved in the development of diabetes and its debilitating vascular complications might bring up more effective and specific clinical therapies. Long-acting glucagon-like peptide (GLP)-1 analogs are currently available in treating diabetes with widely established safety and extensively evaluated efficacy. In recent years, autophagy, as a critical lysosome-dependent self-degradative process to maintain homeostasis, has been shown to be involved in the vascular endothelium damage in diabetes. In this review, the GLP-1/GLP-1R system implicated in diabetic endothelial dysfunction and related autophagy mechanism underlying the pathogenesis of diabetic vascular complications are briefly presented. This review also highlights a possible crosstalk between autophagy and the GLP-1/GLP-1R axis in the treatment of diabetic angiopathy.

Disturbances in copper (Cu) homeostasis have been observed in diabetes and associated complications. Cu is an essential micronutrient that plays important roles in various fundamental biological processes. For example, diabetic cardiomyopathy is associated with elevated levels of Cu in the serum and tissues. Therefore, targeting Cu may be a novel treatment strategy for diabetic complications. This review provides an overview of physiological Cu metabolism and homeostasis, followed by a discussion of Cu metabolism disorders observed during the occurrence and progression of diabetic complications. Finally, we discuss the recent therapeutic advances in the use of Cu coordination complexes as treatments for diabetic complications and their potential mechanisms of action. This review contributes to a complete understanding of the role of Cu in diabetic complications and demonstrates the broad application prospects of Cu-coordinated compounds as potential therapeutic agents.

The incidence of nonalcoholic steatohepatitis (NASH) is related with perfluorooctane sulfonate (PFOS), yet the mechanism remains ill-defined. Mounting evidence suggests that ferroptosis plays a crucial role in the initiation of NASH. In this study, we used mice and human hepatocytes L-02 to investigate the role of ferroptosis in PFOS-induced NASH and the effect and molecular mechanism of PFOS on liver ferroptosis. We found here that PFOS caused NASH in mice, and lipid accumulation and inflammatory response in the L-02 cells. PFOS induced hepatic ferroptosis in vivo and in vitro, as evidenced by the decrease in glutathione peroxidase 4 (GPX4), and the increases in cytosolic iron, acyl-CoA synthetase long-chain family member 4 (ACSL4) and lipid peroxidation. In the PFOS-treated cells, the increases in the inflammatory factors and lipid contents were reversed by ferroptosis inhibitor. PFOS-induced ferroptosis was relieved by autophagy inhibitor. The expression of mitochondrial calcium uniporter (MCU) was accelerated by PFOS, leading to subsequent mitochondrial calcium accumulation, and inhibiting autophagy reversed the increase in MCU. Inhibiting mitochondrial calcium reversed the variations in GPX4 and cytosolic iron, without influencing the change in ACSL4, induced by PFOS. MCU interacted with ACSL4 and the siRNA against MCU reversed the changes in ACSL4，GPX4 and cytosolic iron systemically. This study put forward the involvement of hepatic ferroptosis in PFOS-induced NASH and identified MCU as the mediator of the autophagy-dependent ferroptosis.

Ferroptosis, a new type of programmed cell death proposed in recent years, is characterized mainly by reactive oxygen species and iron-mediated lipid peroxidation and differs from programmed cell death, such as apoptosis, necrosis, and autophagy. Ferroptosis is associated with a variety of physiological and pathophysiological processes. Recent studies have shown that ferroptosis can aggravate or reduce the occurrence and development of diseases by targeting metabolic pathways and signaling pathways in tumors, ischemic organ damage, and other degenerative diseases related to lipid peroxidation. Increasing evidence suggests that ferroptosis is closely linked to the onset and progression of various ophthalmic conditions, including corneal injury, glaucoma, age-related macular degeneration, diabetic retinopathy, retinal detachment, and retinoblastoma. Our review of the current research on ferroptosis in ophthalmic diseases reveals significant advancements in our understanding of the pathogenesis, aetiology, and treatment of these conditions.

Diabetic retinopathy (DR) remains the leading cause of blindness among the global working-age population. Emerging evidence underscores the significance of diabetic retinal neurodegeneration (DRN) as a pivotal biomarker in the progression of vasculopathy. Inflammation, oxidative stress, neural cell death, and the reduction in neurotrophic factors are the key determinants in the pathophysiology of DRN. Non-apoptotic programmed cell death (PCD) plays a crucial role in regulating stress response, inflammation, and disease management. Therapeutic modalities targeting PCD have shown promising potential for mitigating DRN. In this review, we highlight recent advances in identifying the role of various PCD types in DRN, with specific emphasis on necroptosis, pyroptosis, ferroptosis, parthanatos, and the more recently characterized PANoptosis. In addition, the therapeutic agents aimed at the regulation of PCD for addressing DRN are discussed.

The roles of immune cell infiltration and ferroptosis in the progression of proliferative diabetic retinopathy (PDR) remain unclear. To identify upregulated molecules associated with immune infiltration and ferroptosis in PDR, GSE60436 and GSE102485 datasets were downloaded from the Gene Expression Omnibus (GEO). Genes associated with immune cell infiltration were examined through Weighted Gene Co-expression Network Analysis (WGCNA) and CIBERSORT algorithm. Common differentially expressed genes (DEGs) were intersected with ferroptosis-associated and immune cell infiltration-related genes. Localization of cellular expression was confirmed by single-cell analysis of GSE165784 dataset. Findings were validated by qRT-PCR, ELISA, Western blotting, and immunofluorescence staining. As a result, the infiltration of M2 macrophages was significantly elevated in fibrovascular membrane samples from PDR patients than the retinas of control subjects. Analysis of DEGs, M2 macrophage-related genes and ferroptosis-related genes identified three hub intersecting genes, TP53, HMOX1 and PPARA. qRT-PCR showed that HMOX1 was significantly higher in the oxygen-induced retinopathy (OIR) mouse model retinas than in controls. Single-cell analysis confirmed that HMOX1 was located in M2 macrophages. ELISA and western blotting revealed elevated levels of HMOX1 in the vitreous humor of PDR patients and OIR retinas, and immunofluorescence staining showed that HMOX1 co-localized with M2 macrophages in the retinas of OIR mice. This study offers novel insights into the mechanisms associated with immune cell infiltration and ferroptosis in PDR. HMOX1 expression correlated with M2 macrophage infiltration and ferroptosis, which may play a crucial role in PDR pathogenesis.

Ferroptosis is a newly recognized type of programmed cell death that is implicated in the pathophysiological process of neurological disorders. Our previous studies have revealed that exposure to high concentrations of fluoride for long periods of time induces hippocampal neural injury and cognitive deficits. However, whether ferroptosis is involved in fluoride-induced neuronal death and the underlying mechanism remain unknown. In this study, the results indicated that exposure to high fluoride triggered ferroptosis in SH-SY5Y cells and in the hippocampus of mice. Fluoride exposure accelerated the lysosomal degradation of GPX4 and led to neuronal ferroptosis, while GPX4 overexpression protected SH-SY5Y cells against fluoride-induced neurotoxicity. Intriguingly, the enhanced chaperone-mediated autophagy (CMA) induced by fluoride stimulation was responsible for GPX4 degradation because the inhibition of CMA activity by LAMP2A knockdown effectively prevented fluoride-induced GPX4 loss. Furthermore, mitochondrial ROS (mtROS) accumulation caused by fluoride contributed to CMA activation-mediated GPX4 degradation and subsequent neuronal ferroptosis. Notably, the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) or the ROS scavenger N-acetyl-L-cysteine (NAC) alleviated fluoride-evoked hippocampal neuronal death and synaptic injury as well as cognitive deficits in mice. The present studies indicates that ferroptosis is a novel mechanism of fluoride-induced neurotoxicity and that chronic fluoride exposure facilitates GPX4 degradation via mtROS chaperone-mediated autophagy, leading to neuronal ferroptosis and cognitive impairment.