LIFE SCIENCES
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2026
·
IF 5.1
Wei Hua,Yilei Sun,Mingze Sun,Yiying Liu,Hongxue Sun,Huinan Chen,Shuainan Ma
Aims Neuronal ferroptosis affects the pathogenesis of diabetes-associated cognitive decline (DACD). Exogenous hydrogen sulphide (H 2 S) treatment ameliorates cognitive deficits in diabetic mice. This study aimed to explore whether H 2 S exerts neuroprotective effects by suppressing ferroptosis through activation of Nrf2/GPX4 signalling pathway. Materials and methods STZ-induced diabetic mice received NaHS or NaHS combined with the Nrf2 inhibitor ML385, after which cognitive functions were evaluated using the Morris water maze test. Hippocampal neuronal damage and mitochondrial morphological changes were identified using transmission electron microscopy, haematoxylin and eosin (H&E) staining, Nissl staining, and immunofluorescence staining. The expression levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and iron were determined using assay kits. Western blotting was performed to evaluate the expression of the Nrf2/GPX4 axis, iron transport-related proteins, and GSH synthesis enzymes. Key findings Exogenous H 2 S treatment ameliorated cognitive deficits by mitigating hippocampal neuronal loss and improving synaptic ultrastructural integrity. The levels of ROS, MDA, and iron were reduced, whereas SOD, GSH, and Nrf2/GPX4 expression were increased following NaHS administration. Exogenous H 2 S also ameliorated mitochondrial impairment and suppressed ferroptosis in the hippocampal neurones. However, these neuroprotective effects were abolished by ML385. Diabetic mice cotreated with ML385 and NaHS exhibited prolonged escape latency and reduced time in the target quadrant. Additionally, ML385 co-administration with NaHS exacerbated neuronal damage, oxidative stress, synaptic ultrastructural abnormalities, and iron dysregulation, while downregulating Nrf2/GPX4 expression and inhibiting ferroptosis suppression. Significance Exogenous H 2 S treatment alleviates DACD by suppressing ferroptosis via activation of the Nrf2/GPX4 signalling pathway.
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PubMed
高影响因子
Cell Death & Disease
·
2026
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IF 12.2
Song Wei,Zhang Houliang,Wang Yidi,Xu Tianyuan,Ni Jinliang,Wang Guangchun,Zhang Haipeng,Mao Weipu,Wang Keyi,Peng Bo
Clear cell renal cell carcinoma (ccRCC) is a common urological malignancy with limited therapeutic options for advanced disease. Aberrant DNA methylation and dysregulated ferroptosis have both been implicated in ccRCC progression, yet the mechanisms connecting these processes remain incompletely defined. Here, we identify ZBTB10 as a suppressor of ccRCC progression that transcriptionally represses GPX4, a central inhibitor of ferroptosis. Mechanistically, ZBTB10 recruits DNMT1 to the GPX4 promoter, thereby increasing promoter methylation and silencing GPX4 expression. We further define a self-regulatory ZBTB10/DNMT1/FBXW4 loop that maintains this epigenetic state. FBXW4 acts as an E3 ubiquitin ligase that promotes DNMT1 degradation and directly ubiquitinates ZBTB10 to reduce its stability. In turn, ZBTB10 recruits DNMT1 to the FBXW4 promoter, increases promoter methylation, and suppresses FBXW4 transcription. This self-regulatory circuit stabilizes both ZBTB10 and DNMT1, sustains low GPX4 expression, and promotes ferroptosis in ccRCC cells, as evidenced by increased lipid peroxidation and reactive oxygen species accumulation. Together, these findings reveal an epigenetic mechanism linking ZBTB10 to ferroptosis in ccRCC and suggest that targeting the ZBTB10/DNMT1/FBXW4/GPX4 axis may provide a therapeutic strategy for limiting ccRCC progression.
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高影响因子
TOXICON
·
2026
·
IF 2.8
Jing Li,Xiaoxiao Wang,Liya Tu,Yufeng Chen
Ovarian cancer (OC) exhibits the highest mortality rate among gynecological cancers, and the development of chemotherapy resistance serves as the primary cause of patient recurrence and death. Natural products hold promise in reversing cisplatin (DDP) resistance. Trigonelline is a natural alkaloid possessing anti-tumor activity; however, it remains uncertain whether it can reverse DDP resistance in OC. In this study, DDP-resistant OC cell lines SKOV-3/DDP and A2780/DDP were successfully established. Cells were treated with non-toxic concentration of trigonelline in combination with DDP, and the molecular mechanism was investigated through the overexpression of Nrf2. Cell viability was detected to assess the sensitivity of the cells to DDP. Mitochondrial damage was evaluated by observing mitochondrial morphology, measuring mitochondrial membrane potential, ATP production, and ROS. Ferroptosis was assessed by detecting the levels of lipid peroxidation, MDA, SOD, Fe 2+ , and GSH/GSSG ratio in the cells. Additionally, the expression levels of ferroptosis-related proteins, namely Nrf2, HO-1, GPX4, and SLC7A11, were also detected. The results indicated that the utilization of low-concentration trigonelline exerted no toxic influence on OC drug-resistant cells, and instead potentiated the cytotoxicity of DDP against these cells. Furthermore, in comparison with the treatment using DDP alone, the combined treatment of trigonelline and DDP induced more severe mitochondrial damage and ferroptosis in drug-resistant cells. This led to the accumulation of ROS, notable increases in lipid peroxidation, MDA, and Fe 2+ levels within the cells, while decreasing SOD activity and the ratio of GSH/GSSG, and down-regulating the expression of Nrf2, HO-1, GPX4, and SLC7A11 proteins. Nevertheless, the overexpression of Nrf2 reversed the combined effect of trigonelline and DDP. These results indicate that trigonelline reverses DDP resistance in OC cells by promoting ferroptosis via the regulation of the Nrf2/GPX4 signaling pathway.
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PHYTOTHERAPY RESEARCH
·
2025
·
IF 6.3
Li Li,Wenqian Cai,Hao Zhang,Jiuren Tang,Yongjie Yang,Yang Huang,Qing Xi,Rongxin Zhang
Renal fibrosis is the most common pathway for the development of end-stage renal disease (ESRD) in various kidney diseases. Currently, the treatment options for renal fibrosis are limited. Ferroptosis is iron-mediated lipid peroxidation, triggered mainly by iron deposition and ROS generation. Notably, the kidney is the most sensitive of all tissues to iron-dependent ferroptosis, and the inhibition of ferroptosis is an effective therapeutic strategy for the treatment of kidney fibrosis. Nonetheless, the pathways involved in ferroptosis in renal fibrosis are still unclear. Bergapten, a natural coumarin derivative, is mainly found in bergapten essential oil, grapefruit juice, and other commonly used plants, and it has various pharmacological effects. However, the role that ferroptosis plays in renal fibrosis and the potential therapeutic benefits of bergapten remain unclear. In this study, we investigated the therapeutic effects of bergapten on renal fibrosis and its mechanisms. We investigated the anti-fibrotic effects of bergapten in in vivo and in vitro models of renal fibrosis. Initially, network pharmacological analysis was employed to predict the potential therapeutic impact of bergapten on renal fibrosis. We then explored the potential therapeutic role of bergapten in obstructive nephropathy, which is due to unilateral ureteral obstruction (UUO). Furthermore, RNA-Seq was conducted to investigate the possible mechanism of bergapten against renal fibrosis. Additionally, Bergapten demonstrated a significant improvement in TGF-β1-induced fibrosis and RSL3-induced renal tubular epithelial cell ferroptosis; these findings are consistent with those of the in vivo studies. Our findings indicate that bergapten is a potential treatment for renal fibrosis. Treatment with bergapten significantly reduced the expression of fibronectin and α-SMA in the damaged kidneys of UUO mice, thereby improving fibrosis. Meanwhile, bergapten protected against fibrosis caused by TGF-β1 and ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibitor RSL3. Significantly, bergapten therapy alleviated renal fibrosis by modulating ferroptosis. We found that bergapten inhibited PI3K phosphorylation and indirectly restored GPX4 expression. In conclusion, we have revealed the nephroprotective effect of bergapten, whose mechanism of action is related to the inhibition of ferroptosis, and it is expected that it will be developed as a therapeutic agent for the treatment of renal fibrosis. This study aims to explore the effect of bergapten on renal fibrosis ferroptosis. Collectively, these results demonstrate that bergapten is an inhibitor of ferroptosis and provides a new treatment strategy for diseases associated with ferroptosis.
研究领域:
肾病学
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药理学
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分子生物学
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高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2025
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IF 5.4
Lin-Song Teng,Zhen-Dong Ying,Xiao-Han Sun,Hao-Cheng Hou,Shi-Dong Qiu,Peng Liu,Ke-Jing Li,Lei Zhang,Xie-Huang Sheng
Ferroptosis is an iron-dependent form of regulated cell death characterized by lethal lipid peroxidation and implicated in various human diseases. Despite intensive research, clinically applicable ferroptosis inhibitors remain unavailable. In this study, we identify formoterol, a β 2 -adrenergic agonist widely used to treat asthma and COPD, as a potent and selective ferroptosis inhibitor through scaffold-based screening of FDA-approved drugs. Formoterol confers robust protection against ferroptotic cell death induced by diverse triggers across multiple human and rodent cell lines, functioning independently of classical pathways such as GPX4, FSP1, or iron chelation. Mechanistic studies reveal that formoterol suppresses ferroptosis by directly scavenging lipid peroxyl radicals, mediated by its unique ortho -amino phenol moiety. In vivo, formoterol significantly alleviates acetaminophen-induced acute liver injury, reducing hepatic lipid peroxidation and preserving tissue integrity. These findings establish formoterol as a clinically approved agent with previously unrecognized anti-ferroptotic activity, offering a compelling example of drug repurposing to accelerate the development of ferroptosis-targeted therapies.
研究领域:
药理学
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细胞生物学
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肝脏病学
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药物化学
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药物研发
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高影响因子
FITOTERAPIA
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2025
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IF 2.6
Zhong He,Hui Long,Hongyue Ma,Wanrong Ran,Yinhong Song,Wenjuan Shang,Junhui Wang,Ye Qin,Zhangshuang Deng
Triple-negative breast cancer (TNBC) is the most aggressive and malignant breast cancer. Ferroptosis is an oxidative, iron-dependent form of regulated cell death. Ferroptosis-targeted therapies is a promising approach to improving treatment outcomes of TNBC. Combining death pathway inhibitors with relevant indices for ferroptosis and LipROS, this study uncovered that a natural product of 4, 9-dihydroxy- α -lapachone (DLN) from Catalpa bungei “jinsi” exhibited in vitro and in vivo inhibitory activity against TNBC via ferroptosis. The molecular mechanism is an activation of the FTH1 led to iron overload, and then inhibition of cysteine-glutamate antiporter (system Xc − ) and GPX4, which further sensitized TNBC cells to ferroptosis. This study clarified the pathway of DLN-induced cell death in TNBC treatment and exhibited its potential as therapeutic agent for TNBC.
研究领域:
肿瘤学
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分子生物学
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药理学
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高影响因子
Journal of Ovarian Research
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2025
·Vol. 19
·期 1
·8
·
IF 4.2
Ling Xiaomei,Xie Cong,Li Ming,Li Jie,Liu Shun,Sun Liyue,Zeng Xinxin,Zhang Zhen,Zhang Xuhui,Liang Lei
Background Ovarian dysfunction caused by aging restricts female reproductive capacity and causes age-related health problems. Ferroptosis is an important mode of cell death during accelerated aging. Oviductus Ranae (OR), a traditional Chinese medicine, has been used to treat ovarian age-related diseases in women. However, the mechanisms through which OR mitigates ovarian aging, especially ferroptosis regulation, remain unclear. This study investigated the pharmacological effects and mechanisms of OR for ovarian aging in rats. Methods Sprague–Dawley female rats were divided into six groups: aging group induced with D-galactose; experiment groups treated with OR at low, middle, and high concentrations; positive control treated with estradiol valerate; and control group with no treatment. After 42 d, ovarian tissue and serum were collected for biochemical determination, hematoxylin and eosin staining, immunohistochemistry, enzyme-linked immunosorbent assay, reverse transcription-quantitative polymerase chain reaction, western blotting, and RNA sequencing analysis. To elucidate the mechanism underlying the effects of OR on ferroptosis in ovarian granulosa cells (OGCs), in vitro experiments were conducted. Results Treatment with OR improved ovarian follicular development and serum hormone levels, reduced iron deposition, enhanced cell proliferation, and inhibited apoptosis in D-galactose-induced ovarian aging rats. Ferroptosis was alleviated in the ovaries and serum by elevated glutathione and decreased lipid peroxidation production. RNA-seq showed that OR induced changes in 2,768 genes that were involved in ovarian steroidogenesis, glutathione metabolism, lipid metabolism, and ferroptosis pathways. Notably, OR downregulated ACSL4, LPCAT3, and ALOX12 mRNA and protein expressions, while upregulating FTH1, FTL, SLC7A11, GSS, and GPX4, which serve as critical regulators in ferroptosis. OGCs pretreated with OR-containing serum before erastin exposure exhibited enhanced viability, reduced ferrous iron, total iron, and lipid peroxidation levels, improved antioxidant activity, and stabilized mitochondrial function, indicating effective ferroptosis inhibition. Furthermore, OR-containing serum pretreatment inhibited ferroptosis in OGCs by regulating the GPX4/ACSL4 axis. Conclusions OR resists ovarian damage and prevents aging through antiferroptosis mechanisms by regulating the GPX4/ACSL4 axis in OGCs and aging rats. These results highlight the potential of OR as a therapeutic agent for the prevention and treatment of ovarian aging.
研究领域:
药理学
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生殖医学
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细胞生物学
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中医药学
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衰老研究
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PubMed
高影响因子
Food Bioscience
·
2026
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IF 6.2
Yuan Yuan,Yihui Wang,Lu Li,Qingyan Liu,Don Kulasiri,Haiyang Yan
Glycidol (GLD) is a common hazardous contaminant generated during thermal food processing, with well-documented genotoxicity and potential carcinogenicity. GLD is found in many processed foods, such as milk powder, potato chips, and coffee, as a result of the degradation of glyceryl esters (GEs) during heating. In this study, a Balb/c mouse model was used to evaluate the effects of GLD at different doses on neural homeostasis. Exposure to GLD led to reduced weight gain and metabolic disorders in mice. Behavioral assessments further revealed impairments in spatial learning and memory, as well as motor coordination. The in vitro cell model demonstrated that GLD significantly altered the expression of ferroptosis-specific proteins (Nrf2, GPX4, ACSL4), leading to the accumulation of reactive oxygen species (ROS), the inhibition of antioxidant enzyme (SOD, CAT, GSH) activity, and the increase in the level of malondialdehyde (MDA). In addition, GLD induced ferroptosis in brain tissue by inhibiting the Nrf2/GPX4 pathway, disrupting the expression of tight junction proteins (ZO-1, occludin), which in turn increased blood-brain barrier (BBB) permeability. Concurrently, GLD exposure elevated the release of inflammatory factors such as TNF-α and IL-6. Collectively, this study reveals a new mechanism by which GLD impairs BBB function and induces neurobehavioral disorders through ferroptosis, oxidative stress, and neuroinflammation, providing a new avenue for assessing the neurotoxicity by food processing byproducts.
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FISH PHYSIOLOGY AND BIOCHEMISTRY
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2026
·Vol. 52
·期 2
·40
·
IF 3
Zhang Shasha,Li Xinran,Gao Yaxin,Dong Qian,Jin Xiaomin,Shi Pan,Dong Jingquan
Difenoconazole (DFZ) is a persistent triazole fungicide that leads to aquatic toxicity and ecosystem damage due to its environmental persistence and high toxicity. Curcumin (CUR), a natural polyphenol derived from turmeric, exhibits strong anti-inflammatory, antioxidant, and antitumor properties. This study assesses CUR’s protective role against DFZ-induced kidney injury in carp and investigates its mechanisms. Carp were exposed to DFZ for 30 days, with dietary supplementation of 400 mg/kg CUR. H&E staining revealed that CUR significantly reduced DFZ-induced histopathological damage in the kidneys. Dihydroethidium staining and biochemical assays demonstrated that CUR effectively lowered Reactive Oxygen Species levels and lipid peroxidation. Through biochemical kits, qPCR, and Western blotting, it was found that CUR decreased T-AOC and iron content, while activating the Nrf2/HO-1 pathway, thereby alleviating ferroptosis. CUR also upregulated the expression of xCT and GPX4, increased GSH levels, and further suppressed ferroptosis. In terms of inflammation, CUR improved the response by reducing pro-inflammatory cytokines (iNOS, IL-1β, IL-6, TNF-α) and increasing anti-inflammatory factors (IL-10, TGF-β1). With regard to apoptosis, CUR inhibited pro-apoptotic proteins (Bax, Cleaved-caspase3, Cleaved-caspase9, Cytochrome c) and restored the anti-apoptotic protein Bcl-2. In conclusion, CUR alleviates DFZ-induced kidney injury in carp by inhibiting ferroptosis through the Nrf2/GPX4 axis, while reducing oxidative stress, inflammation, and apoptosis. This study highlights CUR as a promising natural agent for mitigating environmental toxicity caused by triazole fungicides. Graphical
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BIOCHEMICAL PHARMACOLOGY
·
2026
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IF 6.5
HaoranZhong,Lei Sun,Jiajun Yu,Yanrong Wang,Tongjie Xu,Tingfeng Yang,Niangkun Liu,Jiayuan Chen,Jinwu Liu,Haochen,Wenguang Fu
Liver regeneration is essential for recovery after major resection or acute injury, yet early regenerative failure remains common. Ferroptosis, an iron-dependent form of lipid peroxidation-driven cell death, impairs hepatocyte survival and may constrain regeneration. Naringenin (NAR), a citrus flavonoid with hepatoprotective activity, has been reported to modulate oxidative stress; however, whether it supports liver regeneration through ferroptosis modulation and which upstream targets are involved remains unclear. Here, hepatocyte models (AML12, Huh7, HepG2) and a murine 70% partial hepatectomy (PHx) model were used to investigate the involvement of PPARα signaling. Proliferation was assessed by CCK-8, EdU, and cell-cycle proteins. Ferroptosis-associated readouts (Fe 2+ , MDA, ROS, GSH) were measured following RSL3 exposure with or without NAR, ferrostatin-1, fenofibrate, or GW6471. Target identification involved network pharmacology, molecular docking, protease protection assay, and CETSA. In PHx mice, NAR was associated with improved liver regrowth (LW/BW ↑25% at 48 h), reduced ALT/AST (∼30–40%), increased proliferation markers, elevated GSH/CAT, and decreased Fe 2+ /MDA. In vitro, NAR increased GPX4/SLC7A11 expression and attenuated RSL3-induced ferroptosis-associated changes. These effects were mimicked by fenofibrate and attenuated by GW6471. NAR was associated with increased PPARα stability and expression. These findings suggest that NAR is associated with reduced ferroptosis and improved liver regeneration, potentially through modulation of PPARα-related signaling, warranting further validation.
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高影响因子
ACS Applied Nano Materials
·
2025
·
IF 5.5
Lin Li,Tiantian Lei,Kejing Wang,Yong Liu,Bingjun Sun,Lin Chen
Chemotherapy has been established as a standard therapeutic regimen for triple-negative breast cancer (TNBC). However, the efficacy of current therapeutic approaches remains suboptimal, primarily attributed to insufficient drug accumulation and the rapid development of chemoresistance. Thus, the rational design of drug delivery systems capable of triggering multimodal cell death pathways represents a promising strategy to combat TNBC. Ferroptosis emerges as a potent form of nonapoptotic cell death, showing great potential for tumor inhibition. The effective codelivery of chemotherapeutic drugs and ferroptosis activators provides potential ideas for the treatment of TNBC. Prodrug-based nanoassemblies have attracted tremendous attention in drug delivery, especially homodimeric prodrugs with ultrahigh drug loading. However, due to their symmetric structures, most homodimeric prodrugs exhibit poor self-assembly ability. Herein, two doxorubicin (DOX) homodimeric prodrugs were designed and coassembled with a GPX4 inhibitor (ML210). The incorporation of ML210 significantly promotes the stability of DOX nanoassemblies and improves the intracellular breakage of the DOX prodrug by regulating the GSH level. As a result, the ML210-driven doxorubicin homodimeric prodrug nanoassemblies exhibit high drug loading capacity, high self-assembly stability, and synergistic chemotherapy-ferroptosis effects. Our results present a viable approach to promote the self-assembly of homodimeric prodrugs while offering an efficient nanoplatform for TNBC treatment.
研究领域:
纳米医学
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癌症治疗
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制药纳米技术
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分子生物学
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肿瘤学
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高影响因子
BME Frontiers
·
2026
·
IF 9.1
Zengfeng Guo,Ningfeng Zhang,Junshen Huang,Wang Zhang,Yawei Hu,Shaochu Chen,Ming Gong,Jianhua Zhou,Jiancheng Yang,Jiawen Wu
Objective: This study aimed to investigate the protective effects and underlying mechanisms of baicalein against iron overload-induced osteoblast dysfunction and bone loss. Impact Statement: This research is the first to demonstrate that baicalein, a natural flavonoid, functions as a dual-action agent combining iron chelation and antioxidation to prevent iron overload-induced ferroptosis in osteoblasts, offering a novel therapeutic strategy for iron overload-related osteoporosis. Introduction: Iron overload contributes to osteoblast damage and osteoporosis through ferroptosis, an iron-dependent cell death pathway. Current treatments fail to simultaneously address iron accumulation and bone loss, highlighting the need for effective dual-function therapies. Methods: Using iron dextran-treated MC3T3-E1 osteoblasts and a murine iron overload model, we assessed the effects of baicalein on cell viability, osteogenic differentiation, ferroptosis markers, and the nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) pathway via biochemical assays, Western blot, and micro-computed tomography. Genetic and pharmacological inhibition of Nrf2 were applied to validate the mechanism. Results: Baicalein chelated iron, scavenged reactive oxygen species, and suppressed ferroptosis in osteoblasts, restoring differentiation under iron overload. It activated Nrf2 nuclear translocation and upregulated GPX4/solute carrier family 7-member 11 (SLC7A11) expression. In mice, baicalein reduced iron deposition, oxidative stress, and bone loss, and these effects were abolished by Nrf2 inhibition. Conclusion: Baicalein alleviates iron overload-induced osteoblast ferroptosis and osteoporosis by activating the Nrf2/GPX4 pathway, supporting its clinical potential as a therapeutic agent for iron-related bone disorders.
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