Alcohol-associated liver disease (ALD) is a prevalent global health issue primarily caused by excessive alcohol consumption. Recent studies have highlighted the gut-liver axis's protective role against ALD, mainly through gut microbiota. However, the precise mechanism remains ill-defined. Our results showed a significant reduction in Lachnospiraceae bacterium in the gut microbiota of ALD patients and ethanol (EtOH)-fed mice, as revealed by 16S rDNA sequencing. Supplementation with Lachnospiraceae bacterium strains in mice significantly reduced inflammation, hepatic neutrophil infiltration, oxidative stress, and improved gut microbiota and intestinal permeability. Multi-omics analysis identified N-Acetyl-glutamic acid (NAG) as the most significantly altered metabolite following Lachnospiraceae bacterium supplementation, with levels positively correlated to Lachnospiraceae bacterium colonization. NAG treatment exhibited significant protective effects in EtOH-exposed hepatocyte cell lines and EtOH-fed mice. Mechanistically, NAG confers hepatoprotection against ALD by activating the KEAP1-NRF2 pathway, inhibiting ferroptosis. Notably, the protective effects of NAG were reversed by the NRF2 inhibitor. In conclusion, oral supplementation with Lachnospiraceae bacterium mitigates alcohol-induced liver damage both in vivo and in vitro by inhibiting ferroptosis through NAG-mediated activation of the KEAP1-NRF2 pathway. Lachnospiraceae bacterium may serve as promising probiotics for future clinical applications.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantial nigra. Mitochondrial dysfunction and mitochondrial oxidative stress are central to the pathogenesis of PD, with recent evidence highlighting the role of ferroptosis - a type of regulated cell death dependent on iron metabolism and lipid peroxidation. Mitochondria, the central organelles for cellular energy metabolism, play a pivotal role in PD pathogenesis through the production of Reactive oxygen species (ROS) and the disruption of iron homeostasis. This review explores the intricate interplay between mitochondrial dysfunction and ferroptosis in PD, focusing on key processes such as impaired electron transport chain function, tricarboxylic acid (TCA) cycle dysregulation, disruption of iron metabolism, and altered lipid peroxidation. We discuss key pathways, including the role of glutathione (GSH), mitochondrial ferritin, and the regulation of the mitochondrial labile iron pool (mLIP), which collectively influence the susceptibility of neurons to ferroptosis. Furthermore, this review emphasizes the importance of mitochondrial quality control mechanisms, such as mitophagy and mitochondrial biogenesis, in mitigating ferroptosis-induced neuronal death. Understanding these mechanisms linking the interplay between mitochondrial dysfunction and ferroptosis may pave the way for novel therapeutic approaches aimed at preserving mitochondrial integrity and preventing neuronal loss in PD.

Swietenia macrophylla King is a traditional medicinal plant extensively utilized in Asia and its pharmacological properties primarily involve antidiabetic, anti-inflammatory, antioxidant, antibacterial, and antitumor effects. Swietenine (Swi), the major bioactive compound presents in the fruits of S. macrophylla, has demonstrated beneficial therapeutic effects on diabetic nephropathy (DN). However, the underlying mechanism through which Swi influences DN remains unclear.

The current research aims to investigate the effects of Swi on DN and explore its underlying mechanisms associated with ferroptosis, both in vivo and in vitro.

A model of streptozotocin/high-fat diet (STZ/HFD)-induced Sprague-Dawley (SD) rats was employed to assess the effect of Swi on improving DN and resisting ferroptosis in vivo. Additionally, mouse podocyte cells (MPC-5 cells) were induced by high glucose (HG) and cultured to explore the potential mechanisms of Swi in treating DN in vitro. To further validate the protective effects of Swi, pathway-specific inhibitors were administered to HG-induced MPC-5 cells to confirm the involvement of the Akt/GSK-3β/Nrf2 signaling pathway in the inhibition of ferroptosis. A combination of proteomics, immunohistochemical staining, western blotting, and cell culture techniques was utilized to explore the pharmacological mechanisms of Swi. Furthermore, network pharmacology and molecular docking analyses were conducted to predict the targets of Swi in relation to DN, which were subsequently validated through Western blotting analysis.

Administration of Swi significantly enhanced renal function and ameliorated pathological alterations in DN rats, as well as improved oxidative stress and inhibited ferroptosis. In vitro studies revealed that Swi dramatically improved the cell viability and mitigated oxidative stress, and inhibited ferroptosis via activating the Akt/GSK-3β/Nrf2 signaling pathway in HG-induced MPC-5 cells.

This study demonstrates that Swi improves DN by inhibiting ferroptosis via activating Akt/GSK-3β/Nrf2 signaling pathway for the first time, thereby providing a scientific basis that Swi is expected to be a promising candidate drug for the treatment of DN.

Ferroptosis has been shown to play a significant role in the pathogenesis of ulcerative colitis (UC). This study investigated the effects of 1,25(OH)2D3 supplementation on ferroptosis in dextran sulfate sodium (DSS)-evoked colitis. Intestinal VDR was reduced in UC patients. Accordingly, GPX4 was downregulated and ACSL4 was upregulated in the intestine of UC patients. Animal experiments indicated that vitamin D deficiency exacerbated DSS-induced intestinal ferroptosis in mice. Conversely, pretreatment with 1,25(OH)2D3 alleviated DSS-induced ferroptosis in mouse intestine. Similarly, 1,25(OH)2D3 supplementation inhibited DSS-induced ferroptosis in HT-29 cells. Furthermore, we found decreased intestinal SIRT3 protein and increased acetylated superoxide dismutase 2 (Ac-SOD2) in UC patients. Pretreatment with 1,25(OH)2D3 attenuated DSS-induced downregulation of SIRT3 and acetylation of SOD2 in both mouse intestine and HT-29 cells. Moreover, 1,25(OH)2D3 pretreatment inhibited mitochondrial reactive oxygen species (mtROS) in DSS-treated HT-29 cells. Finally, transfection with SIRT3 siRNA antagonized the protective effect of 1,25(OH)2D3 on ferroptosis in DSS-treated HT-29 cells. Overall, our results suggest that 1,25(OH)2D3 alleviates DSS-induced intestinal ferroptosis via the SIRT3-SOD2-mtROS pathway, further supporting the potential use of 1,25(OH)2D3 supplementation in UC treatment.

Copper (Cu) is a vital dietary element for both humans and animals and is widely supplemented in food. However, excessive consumption of this trace element can adversely affect the overall well-being. Previous studies have demonstrated that long-term Cu intake can lead to severe hepatotoxicity. The underlying mechanism by which Cu induces disturbances in hepatic energy metabolism through modulation of mitochondria-lipid droplet (LD) contacts, however, is not known. In this study, we found that Cu exposure significantly disrupted the interaction between mitochondria and LDs, leading to the downregulation of perilipin 2 (PLIN2), perilipin 5 (PLIN5), synaptosomal-associated protein 23 (SNAP23), diacylglycerol acyltransferase 2 (DGAT2), and caveolin-1 (Cav-1) proteins in chicken livers. Mechanistically, we demonstrated that Cu exposure-induced dynamin-related protein 1 (DRP1) protein activation disrupted mitochondria-LD contacts by regulating PLIN2. DRP1 knockdown and PLIN2 overexpression efficiently promoted the mitochondria-LD contacts, alleviating Cu-induced LD accumulation in chicken primary hepatocytes. However, PLIN2 knockdown significantly exacerbated the mitochondria-LD contact disorder induced by Cu exposure. Moreover, PLIN2 knockdown dramatically reversed the ability of DRP1 knockdown to promote mitochondria-LD contacts, while overexpression of PLIN2 had the opposite effect. Overall, our study revealed that the DRP1-PLIN2 axis regulates the connections between mitochondria and LDs under Cu exposure, which may provide a new perspective on Cu exposure-induced lipid metabolism disorders in hepatocytes.

Diabetic kidney disease (DKD) is the most common and serious complication of diabetes mellitus. Currently, there is a lack of safe and effective preventive strategies for DKD. The study aimed to explore the preventive effects and potential mechanisms of berberine (BBR) against DKD. In the in vivo experiments, we established a DKD rat model induced by the combination of high-fat diet and streptozotocin to investigate the preventive effect of BBR on DKD. Subsequently, in vitro experiments using human renal tubular epithelial cells (HK-2 cells) were performed to further validate the effect of BBR on renal tubular epithelial cell ferroptosis induced by advanced glycation end products (AGEs). In vivo, we found that BBR improved renal function and attenuated inflammatory cell infiltration, podocyte injury, and iron deposition in renal tissue in DKD rats. In addition, in vitro experiments showed that BBR attenuated HK-2 cell ferroptosis induced by AGEs. We further identified Nrf2 as a direct binding target of BBR by molecular docking and Surface Plasmon Resonance (SPR). Then, immunohistochemistry and Western Blot results demonstrated that BBR could activate the Nrf2 pathway, initiate the endogenous antioxidant system, and inhibit the occurrence of AGEs-induced ferroptosis. Moreover, silencing of Nrf2 by siRNA technology eliminated the protective effect of BBR on AGEs-induced ferroptosis. Collectively, our results supported that BBR could inhibit oxidative stress and ferroptosis by targeting activation of the Nrf2 pathway, thereby delaying the disease progression of DKD, providing a new scientific basis and perspective for the prevention and treatment of DKD.

To explore the benefits of Morinda officinalis oligosaccharides (MOO) on ischemia-reperfusion (I/R) injury and the possible mechanisms involved.

Myocardial I/R injury were induced by left anterior descending branch ligation. MOO pretreatment was given orally 2 weeks prior to ischemic treatment. Echocardiograms, biochemical parameters, and histological and immunohistochemical analyses were used to determine the benefits of MOO on myocardial I/R injury. Oxidative stress and ferroptosis were examined by biochemical parameters, Western blot, immunohistochemistry, and Tunel staining.

MOO improved cardiac function and reduced myocardial oxidative stress and ferroptosis, which was associated with the inhibition of NADPH Oxidase 4 (NOX4) expression. Whereas, the upregulation of NOX4 abolished the benefits of MOO. Furthermore, MOO enhanced mitochondrial superoxide dismutase 2 (SOD2) activity and stimulated the mitochondrial translocation of glutathione peroxidase 4 (mitoGPX4) by inhibiting NOX4. Mitochondria-specific GPX4 overexpression attenuated mitochondrial oxidative stress and suppressed mitochondria-associated ferroptosis in cardiomyocytes that suffered from hypoxia-reoxygenation (H/R) injury, even after NOX4 overexpression.

These results indicate the beneficial effects of MOO on myocardial I/R injury by suppressing oxidative stress and mitochondria-associated ferroptosis through NOX4/mitoGPX4 pathway.

Mitochondria regulate macrophage function, affecting cardiovascular diseases like atherosclerosis and heart failure. Their dynamics interact with macrophage cell death mechanisms, including apoptosis and necroptosis.

This review explores how mitochondrial dynamics and metabolism influence macrophage inflammation and cell death in CVDs, highlighting therapeutic targets for enhancing macrophage resilience and reducing CVD pathology, while examining molecular pathways and pharmacological agents involved.

This is a narrative review that integrates findings from various studies on mitochondrial dynamics and metabolism in macrophages, their interactions with the endoplasmic reticulum (ER) and Golgi apparatus, and their implications for CVDs. The review also considers the potential therapeutic effects of pharmacological agents on these pathways.

The review utilizes a comprehensive literature search to identify relevant studies on mitochondrial dynamics and metabolism in macrophages, their role in CVDs, and the effects of pharmacological agents on these pathways. The selected studies are analyzed and synthesized to provide insights into the complex relationships between mitochondria, the ER, and Golgi apparatus, and their implications for macrophage function and fate.

The review reveals that mitochondrial metabolism intertwines with cellular architecture and function, particularly through its intricate interactions with the ER and Golgi apparatus. Mitochondrial-associated membranes (MAMs) facilitate Ca2+ transfer from the ER to mitochondria, maintaining mitochondrial homeostasis during ER stress. The Golgi apparatus transports proteins crucial for inflammatory signaling, contributing to immune responses. Inflammation-induced metabolic reprogramming in macrophages, characterized by a shift from oxidative phosphorylation to glycolysis, underscores the multifaceted role of mitochondrial metabolism in regulating immune cell polarization and inflammatory outcomes. Notably, mitochondrial dysfunction, marked by heightened reactive oxygen species generation, fuels inflammatory cascades and promotes cell death, exacerbating CVD pathology. However, pharmacological agents such as Metformin, Nitazoxanide, and Galanin emerge as potential therapeutic modulators of these pathways, offering avenues for mitigating CVD progression.

This review highlights mitochondrial dynamics and metabolism in macrophage inflammation and cell death in CVDs, suggesting therapeutic targets to improve macrophage resilience and reduce pathology, with new pharmacological agents offering treatment opportunities.

Diabetic kidney disease (DKD) is one of the major complications of diabetes, and its pathological progression is closely associated with lipid metabolic reprogramming. Under diabetic conditions, renal cells undergo significant lipid metabolic abnormalities, including increased lipid uptake, impaired fatty acid oxidation, disrupted cholesterol efflux, and enhanced lipid catabolism, as adaptive responses to metabolic stress. These changes result in the accumulation of lipids such as free fatty acids, diacylglycerol, and ceramides, leading to lipotoxicity that triggers inflammation and fibrosis. Hypoxia in the DKD microenvironment suppresses fatty acid oxidation and promotes lipid synthesis through the HIF-1α pathway, while chronic inflammation exacerbates lipid metabolic disturbances via inflammatory cytokines, inflammasomes, and macrophage polarization. Targeting lipid metabolism represents a promising therapeutic strategy for alleviating DKD; however, further clinical translational studies are warranted to validate the efficacy and safety of these approaches.

Neuromelanin (NM) is an iron-rich, insoluble brown or black pigment that exhibits protective properties. However, its accumulation over time may render it a source of free radicals. In Parkinson's disease, dopaminergic neurons with the highest NM levels and increased iron content are preferentially vulnerable to degeneration. Considering NM's iron binding capacity and the critical role of iron in ferroptosis, we aimed to investigate the interplay between neuromelanin and ferroptosis in dopaminergic cells. We prepared two NM pigments: iron-free NM (ifNM) and iron-containing NM (Fe3+NM) and, exposed to cells. After verifying NM accumulation, cell viability was assessed in the absence or presence of antioxidants (NAC (1 mM), Trolox (100 μM)) and specific inhibitors of cell death types. Ferroptosis-related parameters, including lipid peroxidation byproducts (4-HNE), lipid ROS, glutathione, intracellular iron, GPX4, and ACSL4, and cellular iron metabolism-related proteins (TfR1, ferroportin, ferritin, IREB2) were evaluated following ifNM and Fe3+NM treatments, with or without Ferrostatin-1, Liproxstatin-1 and deferoxamine. Both NMs induced cell death via distinct mechanisms. Ferroptotic cell death by ifNM and Fe3+NM was reversed by ferrostatin-1 and NAC (p < 0.05). Significant alterations in lipid peroxidation, GPX4 levels, and iron metabolism were observed independent of NM's iron composition (p < 0.05). Ferritin levels increased following ifNM treatment, reflecting an adaptive response to iron overload, while Fe3+NM treatment led to ferritin depletion, possibly via ferritinophagy. Our findings reveal a distinct role of iron-rich and iron-free neuromelanin in modulating ferroptotic pathways, highlighting the potential of targeting neuromelanin-iron interactions as a therapeutic strategy to mitigate neuronal ferroptosis in Parkinson's disease.

Tangshenning (TSN) is a traditional Chinese medicinal formula developed on principles of kidney tonification and collateral unblocking. TSN, formulated from Astragalus mongholicus Bunge, Rheum palmatum L., Ligusticum chuanxiong Hort., and Rosa laevigata Michx., has demonstrated significant clinical efficacy in the treatment of diabetic kidney disease (DKD). Our previous studies have suggested that TSN mitigates tubular injury in DKD by inhibiting ferroptosis, however, the precise molecular targets and mechanistic pathways underlying these effects remain to be fully elucidated.

We investigated whether the Sestrin2/AMPK/PGC-1α axis serves as a key pathway mediating TSN's protective effects against tubular injury in DKD.

In vivo, a spontaneous DKD mouse model was developed using KK-Ay mice. In vitro, human tubular epithelial cells (TECs) were used to establish high glucose and ferroptosis models, as well as a Sestrin2 knockdown model for further analysis. Molecular docking was utilized to examine the binding interactions between TSN's key active components and Sestrin2. Colocalization of Sestrin2 and GPX4 was assessed using dual fluorescence staining. Protein expression levels related to the Sestrin2/AMPK/PGC-1α pathway, ferroptosis markers (SLC7A11 and GPX4), and the tubular injury marker KIM-1 were quantified via Western blot analysis. In vivo, DHE staining, TUNEL staining, and ferrous ion content measurement were performed to evaluate ferroptosis levels in renal tissue. In vitro, the BODIPY 581/591 C11 probe and ferrous ion assay were used to assess ferroptosis levels in TECs. MitoSOX staining, JC-1 assay, and ATP level measurements were conducted to evaluate mitochondrial function in TECs.

In vivo, our results demonstrated that TSN improved renal function, alleviated tubular injury, and reduced pathological damage in DKD mice. Furthermore, TSN upregulated the protein expression of the Sestrin2/AMPK/PGC-1α axis and decreased ferroptosis-related markers in the DKD mouse model. Similarly, in vitro, TSN enhanced the expression of the Sestrin2/AMPK/PGC-1α pathway, restored mitochondrial function, and inhibited ferroptosis in TECs under high glucose and ferroptosis-inducing conditions. Additionally, downregulation of Sestrin2 impaired the therapeutic effects of TSN.

TSN alleviates tubular injury in DKD by activating the Sestrin2/AMPK/PGC-1α pathway, restoring mitochondrial function, and inhibiting ferroptosis in TECs.

Diabetic kidney disease (DKD) is a major diabetic microvascular complication that still lacks effective therapeutic drugs. Ferroptosis is a recently identified form of programmed cell death that is triggered by iron overload. It is characterized by unrestricted lipid peroxidation and subsequent membrane damage and is found in various diseases. Accumulating evidence has highlighted the crucial roles of iron overload and ferroptosis in DKD. Here, we review iron metabolism and the biology of ferroptosis. The role of aberrant ferroptosis in inducing diverse renal intrinsic cell death, oxidative stress, and renal fibrosis in DKD is summarized, and we elaborate on critical regulatory factors related to ferroptosis in DKD. Finally, we focused on the significance of ferroptosis in the treatment of DKD and highlight recent data regarding the novel activities of some drugs as ferroptosis inhibitors in DKD, aiming to provide new research targets and treatment strategies on DKD.

Premature accumulation of senescent cells results in tissue destruction, and it is one of the potential primary mechanisms underlying the accelerated progression of diabetes and periodontitis. However, whether this characterized phenomenon could account for periodontal pathogenesis under hyperglycemic conditions remains unclear. In this study, we assessed the senescent phenotypic changes in experimental periodontitis under hyperglycemic conditions. Next, we investigated the mitochondrial function and the potential mitophagy pathways in cellular senescence in vitro and in vivo. Our findings showed that significant senescence occurred in the gingival tissues of diabetic periodontitis mice with increased expression of senescence-related protein p21Cip1 and the senescence-associated secretory phenotype response as well as the decreased expression of NIP3-like protein X (NIX), a mitochondrial receptor. Likewise, we showed that mitochondrial dysfunction (e.g., reduction of mitochondrial membrane potential and accumulation of reactive oxygen species) was attributed to cellular senescence in: human periodontal ligament cells (hPDLCs) through hyperglycemia-induced and Porphyromonas gingivalis lipopolysaccharide (P.g-LPS)-induced oxidative stresses. Notably, the resulting reduced NIX expression was reversed by the use of the mitochondrial reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine (NAC), thus correcting the mitochondrial dysfunction. We further verified the expression of inflammatory mediators and senescence-related factors in mice gingival tissues and identified the possible regulatory pathways. Taken together, our work demonstrates the critical role of cellular senescence and mitochondrial dysfunction in periodontal pathogenesis under hyperglycemic conditions. Hence, restoration of mitochondrial function may be a potential novel therapeutic approach to tackling periodontitis in diabetic patients.

Ferroptosis is a novel type of programmed cell death dependent on iron and is characterized by the accumulation of lipid peroxides, which is involved in acute lung injury (ALI). Brazilin, an organic compound known for its potent antioxidant and anti-inflammatory properties, has not been thoroughly studied for its potential impact on lipopolysaccharide (LPS)-induced ALI. Here, we found that pretreatment of brazilin mitigated LPS-induced lung injury and inflammation by inhibiting mitochondrial oxidative stress and ferroptosis, both in vivo and in vitro. Sirtuin 3 (SIRT3) was identified as a downstream target of brazilin, and overexpression of SIRT3 mirrored the protective effects of brazilin against LPS-induced ALI. Additionally, SIRT3 contributed to the upregulation, mitochondrial translocation and deacetylation of glutathione peroxidase 4 (GPX4). Through screening potential acetylation sites on GPX4, we identified lysine 148 (K148) as the residue deacetylated by SIRT3. Mutating the acetylation site of GPX4 within mitochondria (mitoGPX4-K148R) reduced LPS or SIRT3 knockdown-induced GPX4 acetylation, oxidative stress, and ferroptosis, ultimately ameliorating ALI. In conclusion, our study demonstrates the beneficial effects of brazilin in treating LPS-induced ALI. Brazilin enhances SIRT3 expression, which in turn deacetylates and facilitates the mitochondrial translocation of GPX4, thereby reducing mitochondrial oxidative stress and ferroptosis. These findings suggest that the SIRT3/GPX4 pathway may represent a critical mechanism, and brazilin emerges as a promising therapeutic candidate for ALI.

Type 4 cardiorenal syndrome (CRS-4) is a pathology in which chronic kidney disease (CKD) triggers the development of cardiovascular disease. CKD pathophysiology produces alterations that can affect the bioenergetics of heart mitochondria, causing oxidative stress and reducing antioxidant glutathione (GSH) levels. GSH depletion alters protein function by affecting post-translational modifications such as S-glutathionylation (RS-SG), exacerbating oxidative stress, and mitochondrial dysfunction. On the other hand, N-acetylcysteine (NAC) is an antioxidant GSH precursor that modulates oxidative stress and RS-SG. Moreover, recent studies have found that NAC can activate the Sirtuin 3 (SIRT3) deacetylase in diseases. However, the role of NAC and its effects on mitochondrial function, redox signaling, and SIRT3 modifications in the heart during CRS-4 have not been studied. This study aimed to investigate the role of NAC in mitochondrial function, redox signaling, and SIRT3 in the hearts of animals with CRS-4 at two months of follow-up. Our results showed that the oral administration of NAC (600 mg/kg/day) improved blood pressure and reduced cardiac fibrosis. NACs' protective effect was associated with preserving cardiac mitochondrial bioenergetics and decreasing these organelles' hydrogen peroxide (H2O2) production. Additionally, NAC increased GSH levels in heart mitochondria and regulated the redox state, which coincided with an increase in nicotinamide adenine dinucleotide oxidized (NAD+) levels and a decrease in mitochondrial acetylated lysines. Finally, NAC increased SIRT3 levels and the activity of superoxide dismutase 2 (SOD-2) in the heart. Thus, treatment with NAC decreases mitochondrial alterations, restores redox signaling, and decreases SIRT3 disturbances during CRS-4 through an antioxidant defense mechanism.

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, plays a pivotal role in various physiological and pathological processes. In this review, we summarize the core mechanisms of ferroptosis, emphasizing its intricate connections to lipid metabolism, including fatty acid synthesis, phospholipid remodeling, and oxidation dynamics. We further highlight advancements in detection technologies, such as fluorescence imaging, lipidomics, and in vivo PET imaging, which have deepened our understanding of ferroptotic regulation. Additionally, we discuss the role of ferroptosis in human diseases, where it acts as a double-edged sword, contributing to cancer cell death while also driving ischemia-reperfusion injury and neurodegeneration. Finally, we explore therapeutic strategies aimed at either inducing or inhibiting ferroptosis, including iron chelation, antioxidant modulation, and lipid-targeted interventions. By integrating mechanistic insights, disease relevance, and therapeutic potential, this review provides a comprehensive perspective on ferroptosis as a crucial interface between lipid metabolism and oxidative stress.

Preeclampsia (PE) is a prevalent obstetric disorder that affects 2-8 % of pregnancies worldwide. Trophoblasts, which are crucial functional cells in the placenta, play a significant role in the development of PE due to inadequate invasion. Sirtuin 3 (SIRT3) is an NAD+ - dependent mitochondrial deacetylase, that positively modulates energy metabolism, mitochondrial biogenesis, and protection against oxidative stress. However, the role of SIRT3 in trophoblast dysfunction and the pathogenesis of PE remains unclear. In this study, we aim to investigate the functional role of SIRT3 in PE and explore the underlying mechanism. Our results demonstrated that human PE placentas exhibited reduced expression of SIRT3. In vitro experiments showed that hypoxia promoted SIRT3 expression, while oxidative stress inhibited SIRT3 expression in HTR-8/SVneo cells. The reduced SIRT3 expression inhibited the proliferation and migration of trophoblast cells while also increasing levels of reactive oxygen species and inflammatory factors. As a deacetylase, SIRT3 deficiency increased the acetylation level of manganese superoxide dismutase (MnSOD), a key mitochondrial antioxidant enzyme, subsequently reducing its activity. These effects associated with reduced SIRT3 expression could be reversed by treatment with MnSOD mimetics TEMPO and overexpression of MnSOD. All these results suggested that diminished SIRT3 expression leaded to MnSOD hyperacetylation and inactivation, contributing to trophoblast dysfunction and the pathogenesis of PE.

Acute kidney injury, a rapid decline in kidney function coupled with physiological and homeostatic perturbations, is an independent risk factor for both short-term and long-term health outcomes. As incidence of acute kidney injury continues to rise globally, the significant clinical and economic challenge of acute kidney injury underscores the need for its prompt recognition and application of novel and germane strategies to reduce its severity and facilitate recovery. Understanding the multifaceted cascade of events engaged in pathogenesis of acute kidney injury is pivotal for the development of effective preventive and therapeutic strategies. To facilitate an in-depth discussion on emerging therapeutic targets, this review will examine the role of macrophages in kidney injury and repair, explore the alterations in mitochondrial biogenesis dynamics induced by acute kidney injury, and provide insights into the molecular mechanisms underlying the contribution of ferroptosis to kidney injury.

Helicobacter pylori (H. pylori) infection is the most common risk factor for gastric cancer (GC). The effect of the antioxidase manganese superoxide dismutase (SOD2) in gastric tumorigenesis remains unclear. We explored the molecular mechanisms of links between H. pylori, inflammation, and SOD2 in GC. We found that SOD2 was upregulated in GC. GC patients with high SOD2 expression showed worse overall survival. H. pylori infection promoted SOD2 expression by transcriptionally activating the NF-κB signaling pathway. Knockdown of SOD2 led to increased levels of reactive oxygen species and oxidative stress in response to H. pylori infection. Our research demonstrates that SOD2 can serve as an inhibitor of ferroptosis by activating AKT, and stabilizing GPX4 protein, which subsequently induces 5-fluorouracil resistance. These findings reveal a mechanism whereby H. pylori can promote gastric carcinogenesis by activating the NF-κB/SOD2/AKT/GPX4 pathway, leading to the inhibition of ferroptosis. This may provide a promising therapeutic target for GC.

Abstract-Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease in neonates, and effective strategies to prevent and treat NEC are still lacking. Studies have shown that N-acetylcysteine (NAC) has protective effects against NEC, however, the specific mechanism underlying its effects on intestinal functions remains unclear. Recently, NAC has been shown to suppress ferroptosis in many diseases, while it is unclear whether the beneficial effects of NAC on NEC are related to ferroptosis. In this study, we revealed that ferroptosis was significantly induced in intestinal samples from infants with NEC. NAC alleviated intestinal inflammation, barrier damage and ferroptosis in multifactorial NEC models in vivo and in vitro. Sestrin2 (SESN2) was identified as an important mediator of NAC-induced ferroptosis resistance in intestinal epithelial cells. Furthermore, SESN2 knockdown inhibited the inflammatory response, alleviated barrier damage and ferroptosis in intestinal epithelial cells and enhanced the protective effects of NAC to a certain extent. Conversely, cells overexpressing SESN2 showed the opposite changes. In summary, our study demonstrated that NAC attenuates NEC progression by decreasing SESN2 expression to inhibit ferroptosis in intestinal epithelial cells, suggesting that NAC might be an effective clinical treatment for NEC.

To explore the influencing factors of acute kidney injury in elderly patients with diabetic nephropathy and to construct a nomogram model.

The research subjects were 680 patients with type 2 diabetic nephropathy admitted to our hospital. The patients were included from May 2018 to August 2023. Patients with acute kidney injury were used as the merge group (n=50), and patients without unmerge group (n=630) was included. The prevalence and predisposing factors of acute kidney injury in diabetic nephropathy were analyzed, multivariate logistic regression were used to analyze the influencing factors of acute kidney injury in patients, and a nomogram risk prediction model was established based on risk factors for verification.

Analysis of the factors of acute kidney injury in diabetic nephropathy found that severe infection was the main trigger, accounting for 40.00%, followed by nephrotoxic antibiotics and severe heart failure. The age, urine microalbumin-to-creatinine ratio (ACR), blood urea nitrogen (BUN), uric acid(UA), and cystatin C (CysC) levels of patients in the combined acute kidney injury group were significantly higher than those in the unmerge group (P<0.05), and the left ventricular ejection fraction (LVEF) and epidermal growth factor receptor (eGFR) levels were significantly lower than those in the unmerge group (P<0.05). Age, ACR, and CysC levels are independent risk factors for acute kidney injury in diabetic nephropathy, and LVEF and eGFR are independent protective factors (P<0.05). The C-index of the nomogram risk prediction model in predicting acute kidney injury in diabetic nephropathy is 0.768 (95% CI: 0.663-0.806), and the calibration curve tends to the ideal curve; the prediction threshold is >0.18, and the nomogram risk prediction model provides a clinical net benefits, and clinical net benefits were higher than independent predictors.

The establishment of a nomogram model for acute kidney injury in elderly patients with diabetic nephropathy based on age, ACR, CysC, LVEF, and eGFR has a good predictive effect, which can help doctors more accurately assess the patient's condition and provide a basis for formulating personalized treatment plans.

The etiology of type 1 diabetes mellitus (T1DM) is intricate, leading to its classification as an autoimmune metabolic disorder. T1DM often coexists with various visceral diseases. N-acetylcysteine (NAC) is widely acknowledged for its potent antioxidant properties. Studies have demonstrated that the combination of NAC and insulin can effectively alleviate iron-induced nephropathy in T1DM and mitigate oxidative stress injury in skeletal muscle associated with the condition. However, the potential impact of NAC alone on liver disease in individuals with T1DM remains uncertain. In this study, a beagle model was established to simulate T1DM, enabling investigation into the role of NAC in liver disease using RNA-seq biogenic analysis and subsequent validation through molecular biological methods. The findings revealed suppressed expression of CXCL12 chemokine in the livers of individuals with T1DM, while treatment with NAC induced specific activation of CXCL12 within the liver affected by T1DM. These results suggest that CXCL12 may serve as a regulatory factor involved in the therapeutic effects of NAC on liver disease associated with TIDM. This discovery holds significant implications for utilizing NAC as an adjunctive therapy for managing complicated liver diseases accompanying type 1 diabetes mellitus.

Nanoplastics (NPs) are an emerging class of pollutants. They can act as a"Trojan horse" to change the bioavailability and toxicity of heavy metals in the environment. However, research on the combined toxicity of heavy metals and NPs is scarce, especially during the critical developmental period of adolescence. In this study, polystyrene nanoplastics (PS-NPs) and/or cadmium (Cd) were exposed to 4-week-old female rats for 28 days, with the aim of exploring the potential effects of combined exposure to PS-NPs and Cd on the ovaries of adolescence rats. Results showed that co-exposure to PS-NPs and Cd exacerbated ovarian toxicity in rats, primarily through increased atretic follicle numbers and endocrine disruption. Further studies revealed that PS-NPs and Cd synergistically repressed the SIRT3-SOD2/Gpx4 pathway, inducing mitochondrial oxidative stress and ferroptosis, resulting in damage to ovarian structure and function. However, the addition of the mitochondrion-targeted antioxidant SS-31 and the ferroptosis inhibitor Fer-1 reversed the harm to the ovaries from co-exposure to PS-NPs and Cd, the aberrant expression of genes related to the SIRT3-SOD2/Gpx4 pathway was also improved. Our results suggested that co-exposure to PS-NPs and Cd may trigger ferroptosis by inhibiting the SIRT3-SOD2/Gpx4 pathway, leading to mitochondrial redox imbalance, which provided novel insights into reproductive toxicity due to the interaction of PS-NPs and Cd during adolescence.

Mizagliflozin (MIZ) is a specific inhibitor of sodium-glucose cotransport protein 1 (SGLT1) originally developed as a medication for diabetes.

To explore the impact of MIZ on diabetic nephropathy (DN).

Diabetic mice were created using db/db mice. They were administered either a low dose (0.5 mg/kg) or a high dose (1.0 mg/kg) of the SGLT1 inhibitor MIZ via stomach gavage for 8 weeks. Subsequently, mesangial cells (MCs) were isolated and subjected to high glucose conditions in culture to assess the effects of MIZ on DN.

The results showed that low doses of MIZ significantly reduced albuminuria to a level comparable to that achieved with high doses in db/db mice. High doses of MIZ led to a substantial increase in body weight in mice, along with decreased blood glucose levels and food intake. Moreover, the intervention with high-dose MIZ notably decreased the expression of extracellular matrix genes, such as collagen type 1 alpha 1 mRNA levels. While the expression of SGLT1 increased after exposure to high glucose, it decreased following treatment with MIZ. Furthermore, MIZ intervention was more effective in improving lactate dehydrogenase levels in MCs induced by high glucose compared to canagliflozin. MIZ also significantly elevated levels of antioxidant enzymes superoxide dismutase, catalase, and glutathione, while reducing malondialdehyde levels.

These findings indicate that MIZ can ameliorate DN by inhibiting SGLT1, inflammation, and oxidative stress.

Ferroptosis, a novel concept of programmed cell death proposed in 2012, in kidney disease, has garnered significant attention based on evidence of abnormal iron deposition and lipid peroxidation damage in the kidney. Our study aim to examine the trends and future research directions in the field of ferroptosis in kidney disease, so as to further explore the target or treatment strategy for clinical treatment of kidney disease.

A thorough survey using the Web of Science Core Collection, focusing on literature published between 2012 and 2024 examining the interaction between kidney disease and ferroptosis was conducted. VOSviewer, CiteSpace, and Biblioshiny were used for in-depth scientometric and visualized analyses.

From 2012 to 2024, a total of 2,244 articles met the inclusion criteria for final analysis. The number of annual publications in this area of study showed a steady pattern at the beginning of the decade. The top 3 journals with the highest publication output were Renal Failure, Oxidative Medicine And Cellular Longevity, and Biomedicine & Pharmacotherapy. China and the United States had the highest number of publications. Central South University and Guangzhou Medical University as the most active and influential institutions. Documents and citation analysis suggested that Andreas Linkermann, Jolanta Malyszko, and Alberto Ortiz are active researchers, and the research by Scott J. Dixon and Jose Pedro Friedmann Angeli, as the most cited article, are more important drivers in the development of the field. Keywords associated with glutathione, lipid peroxidation, and nitric oxide had high frequency in the early studies. In recent years, however, there has been a shift towards biomarkers, inflammation and necrosis, which indicate current and future research directions in this area.

The global landscape of the ferroptosis research in kidney disease from 2012 to 2024 was presented. Basic research and mechanism exploration for renal fibrosis and chronic kidney disease may be a hot spot in the future.

Trehalose has neuroprotective effects in neurodegenerative diseases. This study aimed to explore the impact of trehalose on traumatic brain injury (TBI) by investigating its role in neuroprotection. The TBI mice model was established utilizing the cortical impact technique followed by trehalose treatment. Traumatic neuronal injury induced by scratch followed by trehalose treatment was performed to mimic TBI in vitro. Memory function was assessed using the Water maze test. Brain damage was evaluated through various methods including brain water content analysis, Nissl staining, Evans blue exudation, and TUNEL staining. Biochemical and morphological changes related to ferroptosis post-TBI were also examined. The results showed that trehalose was found to enhance spatial memory, reduce brain injury, and inhibit ferroptosis in TBI mice, similar to ferroptosis inhibitors. The influence of trehalose on TBI was reversed by the SIRT3 inhibitor. Trehalose upregulated SIRT3 to increase SOD activity in TBI, which could also be counteracted by the SIRT3 inhibitor. Combining trehalose with a ferroptosis inhibitor had a more significant effect on reducing brain injury and inhibiting ferroptosis. Furthermore, in TBI mice treated with trehalose and SIRT3 inhibitors, the effect of trehalose was reversed by SIRT3 inhibitors, but the addition of ferroptosis inhibitors reversed the effect of SIRT3 inhibitors, as shown by decreased ferroptosis and neuronal apoptosis in damaged brain tissue. In summary, this study provides initial evidence that trehalose plays a crucial role in neuroprotection post-TBI through the SIRT3/SOD2 pathway-mediated ferroptosis.

The aim of this study was to investigate the effect of curcumin nanocrystals (Cur-NCs) on ferroptosis in high-glucose (HG)-induced HK-2 cells and streptozotocin (STZ)-induced diabetic nephropathy model (DN) rats. The purpose is to determine whether Cur NCs can become a promising treatment option for diabetes nephropathy by reducing ferroptosis.

Cur-NCs were prepared using microfluidic technology and studied using dynamic light scattering and transmission electron microscopy. HK-2 cells were treated with 30 mM HG to create a renal tubule damage cell model. Then, cell viability was evaluated in HK-2 cells treated with varying concentrations of Cur-NCs (0.23, 0.47, 0.94, 1.87, 3.75, 7.5, 15, and 30 μg/mL) using Cell Counting Kit-8 (CCK-8). Furthermore, in vivo experiments were carried out to investigate the roles of Cur-NCs in STZ-induced DN rats.

The results showed that HG treatment greatly enhanced the levels of LDH, MDA, Iron, lipid ROS, apoptosis, NCOA4, TFR-1, while decreasing the expression of GSH, GPX4, SLC7A11, and FTH-1. These effects induced by HG could be attenuated by Cur-NCs. Cur-NCs also reduced the HG-induced decrease in cell viability, as well as the increase in lipid ROS and cell apoptosis, however erastin could inhibit their effects. Furthermore, the in vivo results showed that Cur-NCs reduced ferroptosis and inhibited renal damage in DN rats.

This study demonstrates that Cur-NCs can significantly attenuate ferroptosis in a STZ-induced renal damage model by recovering GPX4, implying that Cur-NCs may be a promising therapy option for DN.

Rampant phospholipid peroxidation initiated by iron causes ferroptosis unless this is restrained by cellular defences. Ferroptosis is increasingly implicated in a host of diseases, and unlike other cell death programs the physiological initiation of ferroptosis is conceived to occur not by an endogenous executioner, but by the withdrawal of cellular guardians that otherwise constantly oppose ferroptosis induction. Here, we profile key ferroptotic defence strategies including iron regulation, phospholipid modulation and enzymes and metabolite systems: glutathione reductase (GR), Ferroptosis suppressor protein 1 (FSP1), NAD(P)H Quinone Dehydrogenase 1 (NQO1), Dihydrofolate reductase (DHFR), retinal reductases and retinal dehydrogenases (RDH) and thioredoxin reductases (TR). A common thread uniting all key enzymes and metabolites that combat lipid peroxidation during ferroptosis is a dependence on a key cellular reductant, nicotinamide adenine dinucleotide phosphate (NADPH). We will outline how cells control central carbon metabolism to produce NADPH and necessary precursors to defend against ferroptosis. Subsequently we will discuss evidence for ferroptosis and NADPH dysregulation in different disease contexts including glucose-6-phosphate dehydrogenase deficiency, cancer and neurodegeneration. Finally, we discuss several anti-ferroptosis therapeutic strategies spanning the use of radical trapping agents, iron modulation and glutathione dependent redox support and highlight the current landscape of clinical trials focusing on ferroptosis.

Chronic kidney disease (CKD) is a multifactorial health issue characterised by kidney impairment that has significant morbidity and mortality in the global population. Current treatments for CKD fail to prevent progression to end-stage kidney disease, where management is limited to renal replacement therapy or kidney transplantation. Mitochondrial dysfunction has been implicated in the pathogenesis of CKD and can be broadly categorised into abnormalities related to excessive oxidative stress, reduced mitochondrial biogenesis, excess mitochondrial fission and dysregulated mitophagy. Mitochondria-targeting therapeutic strategies target many of the outlined mechanisms of mitochondrial dysfunction, and an overview of recent evidence for mitochondria-targeting therapeutic strategies is explored in this review, including naturally derived compounds and novel approaches such as fusion proteins. Mitochondria-targeting therapeutic strategies using these approaches show the potential to stabilise or improve renal function, and clinical studies are needed to further confirm their safety and efficacy in human contexts.

Diabetic nephropathy (DN) is one of the most common complications of diabetes. Our previous study showed that CD38 knockout (CD38KO) mice had protective effects on many diseases. However, the roles and mechanisms of CD38 in DN remain unknown. Here, DN mice were generated by high-fat diet (HFD) feeding plus streptozotocin (STZ) injection in male CD38KO and CD38flox mice. Mesangial cells (SV40 MES 13 cells) were used to mimic the injury of DN with palPagination Donemitic acid (PA) treatment in vitro. Our results showed that CD38 expression was significantly increased in kidney of diabetic CD38flox mice and SV40 MES 13 cells treated with PA. CD38KO mice were significantly resistant to diabetes-induced renal injury. Moreover, CD38 deficiency markedly decreased HFD/STZ-induced lipid accumulation, fibrosis, and oxidative stress in kidney tissue. In contrast, overexpression of CD38 aggravated PA-induced lipid accumulation and oxidative stress. CD38 deficiency increased expression of SIRT3, while overexpression of CD38 decreased its expression. More importantly, 3-TYP, an inhibitor of SIRT3, significantly enhanced PA-induced lipid accumulation and oxidative stress in CD38 overexpressing cell lines. In conclusion, our results demonstrated that CD38 deficiency prevented DN by inhibiting lipid accumulation and oxidative stress through activation of the SIRT3 pathway.

Aims: Diabetic heart damage can lead to cardiomyocyte death, which endangers human health. Baicalin (BAI) is a bioactive compound that plays an important role in cardiovascular diseases. Sentrin/SUMO-specific protease 1 (SENP1) regulates the de-small ubiquitin-like modifier (deSUMOylation) process of Sirtuin 3 (SIRT3) and plays a crucial role in regulating mitochondrial mass and preventing cell injury. Our hypothesis is that BAI regulates the deSUMOylation level of SIRT3 through SENP1 to enhance mitochondrial quality control and prevent cell death, ultimately improving diabetic cardiomyopathy (DCM). Results: The protein expression of SENP1 decreased in cardiomyocytes induced by high glucose and in db/db mice. The cardioprotective effects of BAI were eliminated by silencing endogenous SENP1, whereas overexpression of SENP1 showed similar cardioprotective effects to those of BAI. Furthermore, co-immunoprecipitation experiments showed that BAI's cardioprotective effect was due to the inhibition of the SUMOylation modification level of SIRT3 by SENP1. Inhibition of SENP1 expression resulted in an increase in SUMOylation of SIRT3. This led to increased acetylation of mitochondrial protein, accumulation of reactive oxygen species, impaired autophagy, impaired mitochondrial oxidative phosphorylation, and increased cell death. None of these changes could be reversed by BAI. Conclusion: BAI improves DCM by promoting SIRT3 deSUMOylation through SENP1, restoring mitochondrial stability, and preventing the cell death of cardiomyocytes. Innovation: This study proposes for the first time that SIRT3 SUMOylation modification is involved in the development of DCM and provides in vivo and in vitro data support that BAI inhibits cardiomyocyte ferroptosis and apoptosis in DCM through SENP1. Antioxid. Redox Signal. 42, 53-76.

Osteoarthritis (OA) is one of the leading causes of disability worldwide, characterized by a complex pathological process involving cartilage degradation, synovial inflammation, and subchondral bone remodeling. In recent years, ferroptosis, a form of programmed cell death driven by iron-dependent lipid peroxidation, has been recognized as playing a critical role in the onset and progression of OA. Investigating the molecular mechanisms of ferroptosis and its involvement in OA may offer novel strategies for diagnosing and treating this disease. This review first outlines the core mechanisms of ferroptosis, with a particular focus on the roles of critical molecules such as Glutathione Peroxidase 4 (GPX4), Transferrin Receptor 1 (TfR1), and Nuclear Receptor Coactivator 4 (NCOA4). Subsequently, this study examines the specific impacts of ferroptosis on the pathophysiology of OA. Building on this, the potential of ferroptosis-related biomarkers for OA diagnosis and treatment is highlighted, along with proposed therapeutic strategies targeting ferroptosis regulation. This review aims to deepen the understanding of ferroptosis mechanisms and advance the clinical application of regulatory therapies for OA.

Ferroptosis is an iron-dependent form of programmed cell death associated with lipid peroxidation. Though diabetes worsens cerebral injury and clinical outcomes in stroke, it is poorly understood whether ferroptosis contributes to diabetes-exacerbated stroke. This study aimed to identify ferroptosis-associated differentially expressed genes in ischemic stroke under diabetic condition and then explore their roles using comprehensive bioinformatics analyses.

Type 1 diabetes (T1D) model was established in male mice at 8-10 weeks of age by one intraperitoneal injection of streptozotocin (110 mg/kg). Ischemic stroke was induced by a transient 45-minute middle cerebral artery occlusion and evaluated three days thereafter. Ischemic brain cortex was dissected 24 h after the reperfusion and subjected to bulk tissue RNA sequencing followed by bioinformatics analysis and verification of key findings via quantitative real-time PCR.

Enlarged infarct size was seen in diabetic, as compared with non-diabetic mice, in conjunction with worsened neurological behaviors. Both body and spleen weights were reduced in diabetic as compared with non-diabetic mice. There was a trend for reduced survival rate in diabetic mice following the stroke. In RNA sequencing analysis, we identified 1299 differentially expressed genes in ischemic brain between diabetic and non-diabetic mice, with upregulation and downregulation for 732 and 567 genes, respectively. Among these genes, 27 genes were associated with ferroptosis. Further analysis reveals that solute carrier family 25 member 28(SLC25A28) and sterol carrier protein 2(SCP2) were the top genes associated with ferroptosis in diabetic mice following ischemic stroke. In several bioinformatics analyses, we found SLC25A28, one of the top ferroptosis-related genes, is involved in several metabolic and regulatory pathways as well as the regulatory complexity of microRNAs and circular RNAs, which demonstrates the potential role of SLC25A28 in diabetes-exacerbated stroke. Drug network analysis suggests SLC25A28 as a potential therapeutic target for ameliorating ischemic injury in diabetes.

Our bulk RNA sequencing and bioinformatics analyses show that altered ferroptosis signaling pathway was associated with the exacerbation of experimental stroke injury under diabetic condition. Especially, additional investigation into the mechanisms of SLC25A28 and SCP2 in diabetes-exacerbated stroke will be explored in the future study.

With the widespread use of antimony compounds in synthetic materials and processing, the occupational exposure and environmental pollution caused by antimony have attracted the attention of researchers. Studies have shown that antimony compounds can cause liver damage, but the mechanism has not yet been elucidated. In this study, we used the trivalent potassium antimony tartrate (PAT) to infect L02 hepatocytes and Kunming (KM) mice to establish an antimony-induced apoptosis model of L02 cells and a subacute liver injury model of KM mice. We found that PAT exposure caused hepatocyte apoptosis and was accompanied by oxidative stress and endoplasmic reticulum stress (ERS), and the ERS-associated PERK pathway was activated. Further experimental results showed that N-acetyl-l-cysteine (NAC) pretreatment or silencing of the PERK gene in L02 cells reduced PAT-induced apoptosis. The activity of SOD and CAT in treated L02 cells was increased, the malondialdehyde content in L02 cells and liver tissues was decreased, and the content of ERS-related proteins GRP78 and CHOP, as well as the content of PERK-pathway-related proteins p-PERK/PERK, p-eif2α/eif2α and ATF4 protein were significantly reduced. Overall, PAT exposure triggered hepatocyte apoptosis and liver injury by inducing oxidative stress and activating the ERS-associated PERK pathway; however, this effect could be alleviated by NAC intervention or silencing of PERK in hepatocytes.

Ferroptosis is a nonapoptotic form of cell death characterized by iron-dependent lipid peroxidation in membrane phospholipids. Since its identification in 2012, extensive research has unveiled its involvement in the pathophysiology of numerous diseases, including cancers, neurodegenerative disorders, organ injuries, infectious diseases, autoimmune conditions, metabolic disorders, and skin diseases. Oxidizable lipids, overload iron, and compromised antioxidant systems are known as critical prerequisites for driving overwhelming lipid peroxidation, ultimately leading to plasma membrane rupture and ferroptotic cell death. However, the precise regulatory networks governing ferroptosis and ferroptosis-targeted therapy in these diseases remain largely undefined, hindering the development of pharmacological agonists and antagonists. In this review, we first elucidate core mechanisms of ferroptosis and summarize its epigenetic modifications (e.g., histone modifications, DNA methylation, noncoding RNAs, and N6-methyladenosine modification) and nonepigenetic modifications (e.g., genetic mutations, transcriptional regulation, and posttranslational modifications). We then discuss the association between ferroptosis and disease pathogenesis and explore therapeutic approaches for targeting ferroptosis. We also introduce potential clinical monitoring strategies for ferroptosis. Finally, we put forward several unresolved issues in which progress is needed to better understand ferroptosis. We hope this review will offer promise for the clinical application of ferroptosis-targeted therapies in the context of human health and disease.