LANGMUIR
·
2026
·
IF 4.4
Li Sen,Wang Wentao,Chen Yizhang,Shao Qiuze,Yang Zhaoqi,Hua Dong
Non-small-cell lung cancer (NSCLC) is a lethal malignant
tumor
worldwide. Although ferroptosis offers a promising route for curcumin-mediated
non-small-cell lung cancer therapy, its efficacy is often constrained
by the robust antioxidant defense maintained by the SLC7A11/GSH/GPX4
axis, which continuously sustains cystine uptake, glutathione biosynthesis,
and GPX4-dependent lipid peroxide detoxification, thereby maintaining
cellular homeostasis. Herein, we developed a glutathione-responsive
metal–organic framework nanoplatform for the co-delivery of
curcumin and a GPX4-targeting antisense oligonucleotide (ASO). After
cellular internalization, the disulfide-bearing framework underwent
GSH-triggered disassembly, enabling synchronized release of curcumin
and ASO while depleting the intracellular GSH. Released curcumin increased
ROS accumulation and disturbed redox homeostasis, whereas ASO silenced
GPX4 expression to concurrently disable the antioxidant defense. Flow
cytometry and Western blot assays confirmed significant ROS accumulation
and SLC7A11 downregulation, which were detailed by molecular dynamics
simulations with putative binding modes. Furthermore, the nanocomposite
demonstrated robust anticancer effects in 3D multicellular tumor spheroids
with a promoted oxidative imbalance. Taken together, this coordinated
intervention disrupted the SLC7A11/GSH/GPX4 antioxidant axis, amplified
lipid peroxidation, impaired mitochondrial function, and ultimately
enhanced ferroptotic vulnerability.
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DOI
高影响因子
Cell Death & Disease
·
2026
·
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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DOI
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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高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2025
·
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
·
细胞生物学
·
肝脏病学
·
药物化学
·
药物研发
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产品关联
DOI
PubMed
高影响因子
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
·
药理学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
FITOTERAPIA
·
2025
·
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
·
分子生物学
·
药理学
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产品关联
DOI
PubMed
高影响因子
ChemMedChem
·
2025
·
IF 3.4
Lin Li,Yanyan Wu,Weiwei Wang,Kejing Wang,Lin Chen
Prodrug-based self-assembled nanoassemblies, with carrier-free structures and high drug loading, are garnering attention for chemotherapy. Additionally, the synergistic effects of prodrug nanoassemblies combined with multiple cell death pathways deserve further exploration. Ferroptosis has emerged as a powerful nonapoptotic cell death modality, showing significant potential for tumor inhibition. Therefore, prodrug nanoassemblies combined with ferroptosis inducers may achieve amplified antitumor efficacy. Herein, a GPX4 inhibitor (ML210)-loaded SN38 prodrug nanoparticle system is developed to enhance antitumor efficacy via ferroptotic-chemotherapy synergy. In this system, SN38 is conjugated to 1-octadecanol by a disulfide linkage to construct the self-assembly prodrug. DSPE-PEG 2k is applied to stabilize nanoassemblies. It is proven that ML210 is successfully encapsulated into the SN38 prodrug nanoassemblies by the one-step precipitation method. Both prodrug nanoassemblies exhibit good stability and a GSH-responsive release profile. Furthermore, ML210-loaded nanoassemblies show stronger cytotoxicity, greater proliferation inhibition, and obvious ferroptosis activation. In the CT26 mouse model, ML210-loaded prodrug nanoassemblies demonstrated superior antitumor effects. The strategy—using prodrug as “carriers” for ferroptosis inducers—offers a promising approach for synergistic antitumor therapy. Graphical Redox-responsive SN38-SS-1-octadecanol prodrug was synthesized and used as a “carrier” for ferroptosis activator (ML210). It is proven that ML210 can be successfully encapsulated loaded into the SN38 prodrug nanoassemblies by the one-step precipitation method. Both prodrug nanoassemblies exhibited good stability and a GSH-responsive release profile. The co-assembled system of SN38 prodrug and ML210 can enhance antitumor efficiency by inducing multiple cell death pathway.
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产品关联
DOI
PubMed
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
·
癌症治疗
·
制药纳米技术
·
分子生物学
·
肿瘤学
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DOI
高影响因子
Journal of Ovarian Research
·
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
·
生殖医学
·
细胞生物学
·
中医药学
·
衰老研究
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产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2026
·
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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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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产品关联
DOI
PubMed
高影响因子
FOOD RESEARCH INTERNATIONAL
·
2026
·
IF 8.8
Yueqin Qiu,Shilong Liu,Xinmiao Liao,Wenjing Wang,Jiaxi Tang,Li Wang,Xuefen Yang,Zongyong Jiang
Geniposide alleviated intestinal barrier dysfunction. • Geniposide increased Prevotella copri abundance to alleviate intestinal injury. • Geniposide inhibited diquat-induced intestinal ferroptosis in vivo and in vitro . • Geniposide regulated TRPV4/GPX4-mediated ferroptosis to alleviated intestinal injury. Early weaning disrupts intestinal antioxidant capacity and barrier integrity in human infants and young animals. Geniposide, an iridoid glycoside, exhibits anti-inflammatory and antioxidant activities. However, the mechanism by which geniposide ameliorates weaning-associated intestinal oxidative injury remains to be elucidated. Therefore, this study aimed to investigate whether and how geniposide attenuates intestinal injury, using diquat (DQ)-challenged weaned piglets, mice, and IPEC-J2 cells as experimental models. The results showed that geniposide supplementation significantly alleviated DQ-induced growth inhibition by increasing ADG and ADFI in the piglets. Additionally, geniposide significantly alleviated DQ-induced intestinal barrier damage, as evidenced by increased gene and protein expression of occludin and claudin-1 and decreased intestinal permeability in the ileum. Moreover, geniposide significantly attenuated DQ-induced oxidative stress, as shown by reduced levels of MDA, ROS, and 4-HNE, along with increased activities of T-AOC, GSH-Px, and T-SOD, as well as upregulated protein abundance of NRF2 and GCLM. Microbiome analysis showed that geniposide significantly increased Prevotella copri abundance in the ileum of DQ-challenged piglets. Prevotella copri supplementation alleviated DQ-induced intestinal injury in mice. Transcriptomic and non-targeted metabolomic analyses revealed that geniposide inhibited the DQ-induced ferroptosis signaling pathway. Additionally, geniposide significantly alleviated the DQ-induced the increases in the levels of MDA and Fe 2+ , and restored expression of the anti-ferroptotic proteins GPX4, SLC7A11, and FTL. Mechanistically, geniposide inhibited DQ-induced intestinal ferroptosis through modulation of the TRPV4/GPX4 pathway and increasing Prevotella copri abundance. Collectively, this study revealed that geniposide alleviated DQ-induced intestinal injury by modulating the TRPV4/GPX4-mediated ferroptosis pathway and increasing Prevotella copri abundance, suggesting its potential as a therapeutic agent against weaning-associated intestinal oxidative damage. Download: Download high-res image (117KB) Download: Download full-size image
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高影响因子
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