Cell Discovery
·
2026
·Vol. 12
·期 1
·30
·
IF 16.9
Bai Junping,Geng Dandan,Chen Xinwen,Li Wanting,Wang Xiaowei,Tian Luyang,Han Yi,Jin Zhao,Du Meihang,Tang Yang,Hu Weisheng,Zhu Chunxiao,Zhang Shan,Zhao Zhangting,Zhang Run,Zhang Xinru,Kang Wei,To KaFai,Nomura Sachiyo,Guo Fenghua,Jiao Shi,Xie Yixuan,Zhou Zhaocai,Dong Chao,Li Hui,An Liwei
Protein monoaminylation represents a new layer of neural–cancer regulation, but its role in gastric tumorigenesis is not understood. Using untargeted plasma metabolomics, we revealed that the level of serotonin (5-HT) is significantly elevated in gastric cancer (GC) patients. Functionally, 5-HT treatment dramatically promoted GC cell proliferation and tumor growth in a dose-dependent manner. Importantly, this oncogenic effect was abrogated by the inhibition of transglutaminase 2 (TGM2), indicating a crucial role for protein serotonylation via a receptor-independent mechanism. Using a 5-HT-based chemoproteomic probe, we identified a broad spectrum of serotonylation targets, including key ferroptosis-related proteins such as glutathione peroxidase 4 (GPX4). Specifically, we found that GPX4 is serotonylated by TGM2 at residues Gln55 and Gln77, which increases GPX4 protein stability by attenuating its ubiquitin-mediated degradation, thereby conferring resistance to ferroptosis and facilitating tumor growth. Clinically, TGM2 levels were positively correlated with tumoral GPX4 expression in GC patient specimens. Collectively, our results establish TGM2-mediated GPX4 serotonylation as a key mechanism driving GC progression through ferroptosis resistance, highlighting its potential as both a diagnostic biomarker and a therapeutic target within the neural–tumor axis.
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iScience
·
2025
·
IF 4.1
Kuan Yoow Chan,Yini Yu,Yidi Kong,Ling Cheng,Renzhi Yao,Phoebe Sha Yin Chair,Ping Wang,Rong Wang,Wan-Yang Sun,Rong-Rong He,Junxia Min,Fudi Wang,Mikael Björklund
Despite wide variation, each cell type has an optimal size. Maintaining optimal size is essential for cellular fitness and function but the biological basis for this remains elusive. Here, we performed fitness analysis involving genome-wide CRISPR/Cas9 knockout data from tens of human cell lines and identified that cell size influences the essentiality of genes related to mitochondria and membrane repair. These genes also included glutathione peroxidase 4 (GPX4), which safeguards membranes from oxidative damage and prevents ferroptosis — iron-dependent death. Growth beyond normal size, with or without cell cycle arrest, increased lipid peroxidation resulting in a ferroptosis-sensitive state. Proteomic analysis revealed cell cycle -independent superscaling of endoplasmic reticulum, accumulation of iron and lipidome remodeling. Even slight increases from normal cell size sensitized proliferating cells to ferroptosis as evidenced by deep-learning-based single-cell analysis. Thus, lipid peroxidation may be a fitness trade-off which constrains cell enlargement and contributes to the establishment of an optimal cell size.
研究领域:
细胞生物学
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基因组学
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系统生物学
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癌症研究
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Redox Biology
·
2023
·
IF 11.4
Zhi Xu,Xiumei Wang,Wenbo Sun,Fan Xu,Hengyuan Kou,Weizi Hu,Yanyan Zhang,Qin Jiang,Jinhai Tang,Yong Xu
Tamoxifen (TAM) resistance remains a major obstacle in the treatment of advanced breast cancer (BCa). In addition to the competitive inhibition of the estrogen receptor (ER) signaling pathway, damping of mitochondrial function by increasing reactive oxygen species (ROS) is critical for enhancing TAM pharmacodynamics. Here, we showed that RelB contributes to TAM resistance by inhibiting TAM-provoked ferroptosis. TAM-induced ROS level promoted ferroptosis in TAM-sensitive cells, but the effect was alleviated in TAM-resistant cells with high constitutive levels of RelB. Mechanistically, RelB inhibited ferroptosis by transcriptional upregulating glutathione peroxidase 4 (GPX4). Consequently, elevating RelB and GPX4 in sensitive cells increased TAM resistance, and conversely, depriving RelB and GPX4 in resistant cells decreased TAM resistance. Furthermore, suppression of RelB transcriptional activation resensitized TAM-resistant cells by enhancing ferroptosis in vitro and in vivo . The inactivation of GPX4 in TAM-resistant cells consistently resensitized TAM by increasing ferroptosis-mediated cell death. Together, this study uncovered that inhibition of ferroptosis contributes to TAM resistance of BCa via RelB-upregulated GPX4.
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2024
·
IF 4.2
Wenyuan Yu,Jianghuiwen Lu,Xinqi Huang,Huiru Zhuang,Yumei An,Mingyang Zhang
Background Effective drugs for preventing or treating skin flap necrosis remain elusive. In this study, we investigated the potential protective effect of exendin-4 against skin flap ischemia-reperfusion injury (IRI) through the inhibition of ferroptosis. Method A rat abdomen was constructed with an island skin flap, and the superficial vascular pedicle of the abdominal wall was closed using a vascular clamp, which was removed after 8 h. Before surgery, RSL3 and ferrostatin-1 solutions were intraperitoneally injected. After the surgery, subcutaneous injections of exendin-4 were administered daily. The number of inflammatory cells, mean vascular density, collagen fiber content, and apoptosis and ferroptosis indicators were quantified 24 h after reperfusion. Survival, contraction rate, and blood perfusion of the skin flap were evaluated on days 1, 3, 5, and 7 after reperfusion. Results The flap survival rate was significantly higher in the exendin-4 group than that in the injury group, whereas the contraction rate was lower. Compared with the injury group, the exendin-4 group showed less inflammatory cell infiltration, higher vascular density, and less collagen fiber loss. At the molecular level, the exendin-4 group demonstrated opposite or elevated expression of apoptosis and ferroptosis indicators than those in the injury group, with significantly increased glutathione peroxidase 4 (Gpx4). Ferroptosis inhibitors and agonists enhanced and reversed the protective effects of exendin-4, respectively. Conclusion Exendin-4 alleviates skin flap IRI by upregulating Gpx4 expression to inhibit ferroptosis. Therefore, exendin-4 may serve as a novel clinical treatment for skin flap IRI.
研究领域:
药理学
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外科手术
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分子生物学
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病理学
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FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Wenqi Qian,Xijun Chen,Liuqing Gu,Xiangxiang Lin,Jiawei Chen,Dongchen Xu,Hao Wang,Fucai Long,Qichuan ZhuGe,Peng Zhang,Haoqi Ni
An increasing body of evidence indicates that ferroptosis, characterized by lipid peroxidation (LPO), plays a significant role in the neurophysiological and pathological changes following traumatic brain injury (TBI). Herbacetin (HBT), primarily derived from Sedum plants, is hypothesized to possess strong antioxidant activity due to the presence of five phenolic hydroxyl groups in its structure, which may allow it to counteract ferroptosis after TBI, thereby offering a potential therapeutic approach for TBI treatment. In our study, we employed an erastin and RSL3-induced ferroptosis model using HT22 and PC12 cells. Our findings demonstrated that HBT significantly mitigates erastin-induced cell death by reducing reactive oxygen species (ROS) levels, LPO, and Fe 2+ accumulation. Moreover, HBT protected against changes in mitochondrial membrane potential and mitochondrial superoxide levels induced by erastin and RSL3. We further confirmed HBT’s ability to inhibit ferroptosis in the TBI mouse model. HBT reduced the levels of LPO and iron deposition in the tissue surrounding the injury site after TBI, protected neurons, and decreased microglial activation. Mechanistically, we showed that HBT upregulates hypoxia inducible factor-1α (Hif-1α) expression in both ferroptosis cells and the TBI animal model, which in turn leads to the upregulation of recombinant solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), thereby reducing ferroptosis. RNA-seq analysis and Hif-1α knockdown experiments in HT22 cells supported this conclusion. In conclusion, our findings provide a potential therapeutic basis for the clinical use of HBT in preventing neuronal ferroptosis following TBI.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 4.7
Yan Song,Mi Chen,Chen Wu,Leiming Yang,Qiyu Sun,Shuang Guo,Huiting He,Qi Huang,Xiying Guo,Youzhi Zhang
Trimethyltin chloride (TMT) is a highly toxic organotin pollutant commonly found in the environment, posing serious risks to humans and animals. To explore the potential toxicity mechanism of TMT on vascular systems, we developed models exposing vascular smooth muscle cells (VSMCs) and male Balb/c mice to TMT. Levels of reactive oxygen species (ROS) and glutathione (GSH) were measured using fluorescence methods and assay kits, while the expression of genes related to glutathione peroxidase 4 (GPX4), Nuclear factor (erythroid-derived 2)-like 2/heme oxygenase-1 (NRF2/HO-1) pathway, autophagy-lysosome, and ubiquitination proteasome pathway were analyzed through Western blot and immunofluorescence. The findings indicated that exposure to TMT activated the GPX4-dependent lipid peroxidation pathway, leading to cell death in VSMCs, rather than necrosis or apoptosis. This conclusion was supported by several key indicators: a dose-dependent increase in ROS levels, alongside a dose-dependent decrease in GSH and GPX4 levels. Further in-depth analysis elucidated that TMT-induced GPX4 degradation and subsequent cell death are primarily mediated by the ubiquitination-proteasome pathway. Notably, this process occurs independently of the NRF2/HO-1 signaling pathways or the autophagy-lysosome system. In conclusion, TMT exposure causes dose-dependent GPX4 degradation via the ubiquitination proteasome pathway, leading to cell death in VSMCs and vascular injury.
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BIOMEDICINE & PHARMACOTHERAPY
·
2022
·
IF 7.419
Ya Zhang,Qifang Wu,Jian Liu,Zhongshan Zhang,Xiaojing Ma,Yaoyue Zhang,Jiawen Zhu,Ronald W. Thring,Mingjiang Wu,Yitian Gao,Haibin Tong
Insulin resistance is a characteristic feature of type 2 diabetes. Sulforaphane (SFN) is a natural antioxidant extracted from the cruciferous vegetables. Recent study reported that SFN exhibits excellent anti-diabetic effects, however, the underlying mechanism is still unclear. This study aimed to investigate the therapeutic effects of SFN on a high-fat diet (HFD)-induced insulin resistance and potential mechanism. SFN was found to effectively reduce body weight, fasting blood glucose and hyperlipidemia, and improve liver function in HFD-fed mice. Furthermore, SFN effectively increased glucose uptake and improved insulin signaling in palmitic acid (PA)-induced HepG2 cells. SFN also led to increased expression of antioxidant genes downstream of Nrf2 and decreased accumulation of lipid peroxides MDA and 4-HNE, both in vivo and in vitro. Further studies revealed that SFN significantly reduced glutathione peroxidase 4 (GPx4) inactivation-mediated oxidative stress by activating the AMPK and Nrf2 signaling pathways. In PA-induced HepG2 cells and flies , the alleviation of insulin resistance by SFN was diminished by GPx4 inhibitor. Taken together, SFN ameliorated HFD-induced insulin resistance by activating the AMPK-Nrf2-GPx4 pathway, providing new insights into SFN as a therapeutic compound for the alleviation of insulin resistance.
研究领域:
药理学
·
内分泌学
·
分子生物学
·
营养学
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IUBMB LIFE
·
2021
·Vol. 73
·期 9
·1180-1190
·
IF 3.885
Jing Wang,Tao Wang,Yang Zhang,Jiaqi Liu,Jie Song,Yanlong Han,Lihong Wang,Shuang Yang,Lili Zhu,Rui Geng,Weimin Li,Xiaoguang Yu
The induction of ferroptosis is considered a new strategy for cancer treatment. Cytoplasmic polyadenylation element binding protein 1 (CPEB1) is a post-transcriptional regulatory factor, whose low expression has been reported to link to the enhanced metastasis and angiogenesis of gastric cancer (GC). In this study, to explore the role of CPEB1 in ferroptosis, GC cells with overexpressed or silenced CPEB1 expression were treated with erastin, a classic ferroptosis inducer. The results showed that erastin dose-dependently decreased the viability of four GC cell lines (AGS, SNU-1, Hs-746 T, and HGC-27), suggesting that ferroptosis could be triggered in these GC cells. Interestingly, HGC-27 cells overexpressing CPEB1 were more sensitive to erastin, generated more lipid reactive oxygen species (ROS) and malondialdehyde (MDA), and their glutathione peroxidase 4 (Gpx4) expression and GSH content were reduced. Contrarily, CPEB1-silenced AGS cells were more resistant to erastin. Mechanically, we demonstrated that CPEB1 overexpression reduced the expression of twist1, an inhibitor of activating transcription factor 4 (ATF4), thereby activating the ATF4/ChaC Glutathione Specific Gamma-Glutamylcyclotransferase 1 (CHAC1) pathway (CHAC1, a molecule known to induce GSH degradation). Furthermore, re-expression of twist1 in GC cells impaired the effects of CPEB1 overexpression in presence of erastin. Additionally, similar to the in vitro results, the growth-inhibiting effects of erastin on GC xenografted tumors were also augmented by CPEB1 overexpression in vivo. Collectively, we demonstrate that CPEB1 facilitates erastin-induced ferroptosis by inhibiting twist1.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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Communications Biology
·
2026
·
IF 5.8
Kunpeng Jia,Yuxin Ding,Menglei Jin,Qi Yang,Xinyu Wang,Yujie Yan,Jiao Xiang,Ruoqi Zhang,Jun Fang,Jingxin Jiang,Danting Wang,Fengbo Huang,Jianming Hu,Jian Huang,Yeting Hu,Zhigang Chen
Chemotherapy resistance remains a major challenge in advanced colorectal cancer (CRC), with chemotherapy-induced senescence playing a key role. While cancer cell senescence has been extensively studied, the contribution of stromal components, particularly vascular endothelial cells, remains unclear. Here, we analyze 77 CRC patients undergoing neoadjuvant chemotherapy and find that favorable responders exhibit well-defined vascular lumens, whereas poor responders show an increase in senescent endothelial cells (senEndo), as revealed by single-cell transcriptomics and immunofluorescence. Chemotherapy-induced senescence reduces GPX4 ubiquitylation in senEndo, leading to its accumulation and extracellular vesicle transfer to CRC cells, where it inhibits ferroptosis and promotes chemoresistance. In vitro and in vivo models demonstrate that targeting GPX4 with the ferroptosis activator RSL3 restores chemotherapy sensitivity. These findings identify a novel mechanism of chemoresistance mediated by senEndo-derived GPX4 in extracellular vesicles and highlight the potential of ferroptosis induction, alone or in combination with senolytic agents, to improve 5-Fu/oxaliplatin-based CRC therapies. Extracellular vesicles from senescent endothelial cells transfer GPX4 to colorectal cancer cells, suppress ferroptosis, and promote resistance to neoadjuvant chemotherapy
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FASEB JOURNAL
·
2026
·Vol. 40
·期 14
·e72154
·
IF 4.3
Ya‐Ping Li,Fei‐Hong Huang,Meng‐Ting Wu,Meng‐Yi Chen,Yong‐Ping Wen,Xiang Li,Lu Yu,An‐Guo Wu,Jian‐Ming Wu,Xiao‐Gang Zhou
Ferroptosis contributes to aging‐associated functional decline, yet compounds with robust organismal efficacy and defined upstream regulatory mechanisms remain limited. Here, we established a diethyl maleate (DEM)‐induced glutathione depletion model in wild‐type (N2) Caenorhabditis elegans as a survival‐based screening platform and identified syringaresinol (Syr) as a leading hit from an in‐house small‐molecule library. In nematodes, Syr improved survival under DEM challenge, reduced lipid peroxidation, reactive oxygen species (ROS), and malondialdehyde levels, and alleviated age‐associated oxidative lipid stress and iron imbalance during natural aging, accompanied by extended lifespan and improved healthspan‐related phenotypes. In primary human foreskin fibroblasts, Syr conferred dose‐dependent protection against RSL3‐ or erastin‐induced ferroptosis, preserved cellular integrity, suppressed lipid peroxidation and ROS, and restored expression of GPX4, SLC7A11, and ferritin. In two senescence models, Syr also attenuated senescence‐associated phenotypes and ferroptosis‐related oxidative lipid stress, concomitant with recovery of GPX4 expression. Network‐based prediction and functional perturbation identified HIF‐1α as a candidate mediator of Syr‐associated cytoprotection. HIF‐1α knockdown weakened Syr‐mediated protection and largely prevented GPX4 restoration, whereas GPX4 knockdown did not alter HIF‐1α abundance. These findings support a functional HIF‐1α–GPX4 defense axis in fibroblasts, while direct transcriptional regulation remains to be clarified. Overall, Syr attenuates ferroptosis‐relevant oxidative lipid stress and aging‐associated phenotypes in C. elegans and human fibroblast models, supporting further mechanistic and mammalian in vivo validation. A 220‐compound screen in DEM‐challenged C. elegans identified syringaresinol (Syr) as a lead protective compound. Syr alleviated aging‐ and ferroptosis‐associated phenotypes in C. elegans and human foreskin fibroblasts by reducing lipid peroxidation, ROS accumulation, MDA levels, labile Fe 2+ , cell death, and SA‐β‐gal activity, while restoring GPX4/SLC7A11/ferritin‐associated defense responses. The proposed mechanism suggests that Syr attenuates senescence‐associated functional decline through a HIF‐1α‐associated GPX4 protective axis. The dashed arrow denotes a hypothesized mediator or interaction that remains to be experimentally validated.
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JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY
·
2026
·Vol. 40
·期 7
·e70982
·
IF 3.6
Zimeng Liu,Yunpeng Gao,Musen Li,Qingsong Sun,Yunhe Fu,Yue Zhang
Mastitis is a prevalent gynecological disorder in women, with Staphylococcus aureus ( S. aureus ) serving as a primary etiological pathogen of this condition. Cryptotanshinone (CPT) has been demonstrated to exert anti-oxidative stress and anti-inflammatory effects, conferring therapeutic benefits for a diverse range of inflammatory diseases. However, its efficacy and underlying regulatory mechanisms in ameliorating S. aureus -induced mastitis remain elusive. Therefore, the present study was designed to elucidate the protective effects and molecular regulatory mechanisms of CPT against S. aureus -induced mastitis. A murine model of S. aureus -induced mastitis was established via intramammary injection of S. aureus , and CPT was administered to the model mice for therapeutic intervention. In vivo experiments revealed that CPT administration mitigated S. aureus -induced mastitis in mice by suppressing the production of pro-inflammatory cytokines and inhibiting ferroptosis. In vitro, CPT abrogated the S. aureus -induced elevation of TNF-α, IL-1β, MDA, ROS, and Fe 2+ levels in mouse mammary epithelial cells (MMECs); additionally, it restored the ATP and GSH levels that were reduced by S. aureus stimulation in these cells. Furthermore, CPT concentration-dependently upregulated the expression of GPX4, Nrf2 and HO-1 in MMECs. Notably, the inhibitory effects of CPT on S. aureus -induced inflammatory responses and ferroptosis were abrogated in Nrf2-knockdown MMECs. In conclusion, this study demonstrates that CPT exerts a robust protective effect against S. aureus -induced mastitis by suppressing inflammatory responses and inhibiting ferroptosis through the activation of the Nrf2/GPX4 signaling pathway.
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Autophagy
·
2026
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IF 18.6
Xi Chen,Shuhan Liu,Mengqi Jiang,Mingyu Wei,Shuwan Xu,Jin-Yi Lin,Ze-Bo Huang,Pengxin Xie,Jixiang Cao,Hua Yang,Yun Bai,Guang Lu,Ming Cui
Mitochondrial damage is a pivotal driver of myocardial ischemia-reperfusion (MIR) injury. While PRKN (parkin RBR E3 ubiquitin protein ligase), a key E3 ubiquitin ligase in the PINK1 (PTEN induced kinase 1)-PRKN mitophagy pathway, has been extensively studied, its role and mechanisms in acute MIR injury remain incompletely understood. Here, we demonstrated that PRKN exacerbates MIR injury by promoting cardiomyocyte ferroptosis under hypoxia-reoxygenation (H/R) conditions. Mechanistically, PRKN interacts with and mediates the ubiquitination and proteasomal degradation of IMMT/MIC60 (inner membrane mitochondrial protein), a core mitochondrial inner membrane protein essential for cristae architecture and mitochondrial integrity. This disruption of IMMT facilitates lysosomal degradation of GPX4 (glutathione peroxidase 4), a major ferroptosis suppressor, thereby triggering ferroptosis. Consistent with these findings, cardiac-specific immt knockout mice displayed increased susceptibility to MIR injury in vivo. Our findings establish PRKN-driven IMMT degradation as a key pathological mechanism in MIR injury and identify the PRKN-IMMT axis as a potential therapeutic target for cardioprotection. Abbreviations: ATG5, autophagy related 5; ATP, adenosine triphosphate; CCCP, carbonyl cyanide m-chlorophenylhydrazone; CHX, cycloheximide; cKO, cardiomyocyte-specific knockout; CQ, chloroquine; CRISPR, clustered regularly interspaced short palindromic repeats; EF, ejection fraction; Fer-1, ferrostatin-1; FS, fractional shortening; GO, Gene Ontology; GPX4, glutathione peroxidase 4; GST, glutathione S-transferase; gRNA, guide RNA; hiPSC-CMs, human induced pluripotent stem cell-derived cardiomyocytes; H/R, hypoxia-reoxygenation; IF, immunofluorescence; IHC, immunohistochemistry; IMMT/MIC60, inner membrane mitochondrial protein; IP, immunoprecipitation; LoxP, locus of X-overP1; KO, knockout; KR, lysine residues mutated to arginine; MDA, malondialdehyde; MFN2, mitofusin 2; MIR, myocardial ischemia reperfusion; MMP, mitochondrial membrane potential; mPTP, mitochondrial permeability transition pore; mtROS, mitochondrial reactive oxygen species; NAC, N-acetylcysteine; OMM, outer mitochondrial membrane; PRKN, parkin RBR E3 ubiquitin protein ligase; RAB7, RAB7, member RAS oncogene family; RNA-seq, RNA sequencing; UB, ubiquitin; WB, western blot; WT, wild-type.
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