Advanced Science
·
2024
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IF 14.3
Jingxuan Cui,Yujia Chen,Qiannan Yang,Peng Zhao,Mian Yang,Xiaoqi Wang,Ge Mang,Xiangyu Yan,Di Wang,Zhonghua Tong,Penghe Wang,Yingjin Kong,Naixin Wang,Dongni Wang,Nana Dong,Mingyang Liu,Mingyan E,Maomao Zhang,Bo Yu
Doxorubicin (DOX) is an effective anticancer agent, but its clinical utility is constrained by dose-dependent cardiotoxicity, partly due to cardiomyocyte ferroptosis. However, the progress of developing cardioprotective medications to counteract ferroptosis has encountered obstacles. Protosappanin A (PrA), an anti-inflammatory compound derived from hematoxylin, shows potential against DOX-induced cardiomyopathy (DIC). Here, it is reported that PrA alleviates myocardial damage and dysfunction by reducing DOX-induced ferroptosis and maintaining mitochondrial homeostasis. Subsequently, the molecular target of PrA through proteome microarray, molecular docking, and dynamics simulation is identified. Mechanistically, PrA physically binds with ferroptosis-related proteins acyl-CoA synthetase long-chain family member 4 (ACSL4) and ferritin heavy chain 1 (FTH1), ultimately inhibiting ACSL4 phosphorylation and subsequent phospholipid peroxidation, while also preventing FTH1 autophagic degradation and subsequent release of ferrous ions (Fe 2+ ) release. Given the critical role of ferroptosis in the pathogenesis of ischemia-reperfusion (IR) injury, this further investigation posits that PrA can confer a protective effect against IR-induced cardiac damage by inhibiting ferroptosis. Overall, a novel pharmacological inhibitor is unveiled that targets ferroptosis and uncover a dual-regulated mechanism for cardiomyocyte ferroptosis in DIC, highlighting additional therapeutic options for chemodrug-induced cardiotoxicity and ferroptosis-triggered disorders.
研究领域:
药理学
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心脏病学
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肿瘤学
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分子生物学
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生物化学
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DOI
PubMed
高影响因子
Redox Biology
·
2022
·
IF 10.787
Yue Wang,Menghan Zhang,Ran Bi,Yali Su,Fei Quan,Yanting Lin,Chongxiu Yue,Xinmeng Cui,Qixiang Zhao,Siliang Liu,Yong Yang,Dayong Zhang,Qiuhua Cao,Xinghua Gao
The term ferroptosis coined in 2012 causes acute kidney injury (AKI). However, its pathway mechanism in AKI is poorly understood. In this study, we conducted an RNA-sequence analysis of kidneys in AKI and normal mice to explore the pathway mechanism of ferroptosis. Consequently, differentially expressed genes highlighted Acyl-CoA synthetase long-chain family (ACSL4), a known promotor for ferroptosis. Besides, RT-PCR, Western blot, and immunohistochemical analyses confirmed its upregulation. HIF-1α was downregulated in I/R-AKI mice, and in vitro studies confirmed a negative regulation of HIF-1α on ACSL4. To explore the role of ACSL4 in AKI, we constructed ACSL4 knockout in kidney tubules of mice-as Cdh16Cre-ACSL4 F/F mice. Results revealed that ACSL4 knockout significantly reduced ferroptosis and inhibited the functional and pathological injury of AKI mice. Meanwhile, the kidneys of Cdh16Cre-ACSL4 F/F mice demonstrated a significantly decreased inflammation and macrophage infiltration. Further, additional explorations were explored to decipher a more thorough understanding of ferroptotic immunogenicity. As a result, neutrophils were not directly recruited by ferroptotic cells, but by ferroptotic cell-induced macrophages. Further, ACSL4 inhibitor rosiglitazone significantly inhibited AKI. Collectively, these data provide novel insights into the AKI pathogenesis, and defined ACSL4 as an effective target in AKI.
研究领域:
肾病学
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分子生物学
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病理学
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DOI
PubMed
高影响因子
iScience
·
2022
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IF 6.107
Kun Fang,Sha Du,Dachuan Shen,Zhipeng Xiong,Ke Jiang,Dapeng Liang,Jianxin Wang,Huizhe Xu,Lulu Hu,Xingyue Zhai,Yuting Jiang,Zhiyu Xia,Chunrui Xie,Di Jin,Wei Cheng,Songshu Meng,Yifei Wang
Summary Ferroptosis is a new kind of regulated cell death that is characterized by highly iron-dependent lipid peroxidation. Cancer cells differ in their sensitivity to ferroptosis. Here we showed that the Suppressor of fused homolog (SUFU), a critical component in Hedgehog signaling, regulates ferroptosis sensitivity of breast cancer cells. Ectopic SUFU expression suppressed, whereas depletion of SUFU enhanced the sensitivity of breast cancer cells to RSL3-triggered ferroptosis through deregulation of ACSL4. Moreover, SUFU depletion promoted the activation of Yes-associated protein (YAP), thereby increasing the expression of ACSL4. Mechanistically, SUFU is associated with LATS1. Deletion of a region comprising residues 174–385 in SUFU disrupted SUFU binding to LATS1, thus abrogating SUFU-mediated downregulation of the YAP-ACSL4 axis and sensitivity to ferroptosis. Noteworthy, we showed that vincristine downregulated SUFU, thus increasing breast cancer cell sensitivity to RSL3 in vitro and in vivo . Together, our findings uncover SUFU as a novel regulator in ferroptosis sensitivity.
研究领域:
癌症生物学
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细胞信号传导
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分子生物学
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肿瘤学
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DOI
PubMed
高影响因子
CANCER SCIENCE
·
2026
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IF 4.9
Jing Yang,Puyuan Chen,Yawen Zheng,Feiyue Shi,Min Wang,Luwei Xu,Xiaowei Wei,Xiumei Wang
Radioresistance in prostate cancer demands innovative sensitization strategies. We identified the glucocorticoid receptor nuclear receptor subfamily 3 group C member 1 (NR3C1) as a key negative regulator of radiosensitivity linked to poor prognosis. NR3C1 transcriptionally upregulates the lipid-metabolizing enzyme, acyl-CoA synthetase long-chain family member 4 (ACSL4), thereby enhancing cell proliferation, migration, and radioresistance. High ACSL4 expression sensitizes cells to ferroptosis inducers that amplify lipid peroxidation and restore radiosensitivity. Using the clinically applicable ferroptosis inducer, dihydroartemisinin (DHA), we found that DHA synergizes with ACSL4 to trigger ferroptosis, sensitizing radioresistant cells and xenografts to radiation. This effect was characterized by elevated lipid peroxidation and was reversed by the ferroptosis inhibitor deferoxamine. Collectively, our study revealed that the NR3C1-ACSL4 axis regulates lipid peroxidation and promotes radioresistance. Targeting this axis with DHA and using ACSL4 as a biomarker represents a promising preclinical strategy to overcome radioresistance in prostate cancer, pending further clinical validation.
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PubMed
高影响因子
Cell Discovery
·
2025
·Vol. 11
·期 1
·1-17
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IF 12.5
Shan Guangyao,Bian Yunyi,Sui Qihai,Liang Jiaqi,Ren Shencheng,Pan Binyang,Shi Haochun,Zheng Zhaolin,Zeng Dejun,Zhu Junkan,Chen Zhencong,Bi Guoshu,Fan Hong,Zhan Cheng
Lactylation, a lactate-mediated post-translational modification, has garnered significant attention for its pivotal role in epigenetic modulation. However, the intricate interplay between lactylation and ferroptosis in lung adenocarcinoma (LUAD) remains to be fully elucidated. Utilizing metabolomic profiling and comprehensive metabolic library screening, our study uncovers that ferroptosis markedly enhances lactic acid accumulation and subsequent protein lactylation, which in turn confers resistance to ferroptosis in LUAD cells. Functional assays, comprising cell viability tests, lipid peroxidation detection, as well as malondialdehyde and glutathione measurements, collectively reveal that SUMO2-K11 lactylation (SUMO2-K11la), the most prominently elevated lactylation in response to ferroptosis induction, serves as a pivotal factor in determining ferroptosis resistance. Sumoylation proteomics and co-immunoprecipitation assays reveal that SUMO2-K11la impairs the interaction between SUMO2 and ACSL4. Consequently, this disruption facilitates the degradation of ACSL4, thereby disrupting lipid metabolism and effectively mitigating ferroptosis. Furthermore, AARS1 is identified as the lactyltransferase and HDAC1 as the delactylase for SUMO2-K11la. Based on these findings, we develop a cell-penetrating peptide that competitively and specifically inhibits SUMO2-K11la. This peptide significantly potentiates ferroptosis and sensitizes LUAD to cisplatin in xenograft models, while enhancing chemoimmunotherapy responses in spontaneous lung cancer models. Overall, our findings imply that SUMO2-K11la is a pivotal regulator of ferroptosis resistance in LUAD, and suggest a promising strategy to potentiate ferroptosis-based cancer therapies via targeting SUMO2-K11la by the cell-penetrating peptide.
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DOI
PubMed
高影响因子
CELL DEATH AND DIFFERENTIATION
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2025
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IF 15.4
Fan Kexin,Zhou Shuting,Ren Yakun,Xiong Jingwen,Wang Hua,Fu Yaxin,Chen Yuhan,Wang Bobo,Fan Kun,Gao Min,Guo Tingli,Wei Xiaofeng,Jiao Lianying,Shi Jiejun,Ding Chenguang,Zhang Yilei
The tumor suppressor BRCA1-associated protein 1 (BAP1) encodes a nuclear deubiquitinase that specifically removes H2A monoubiquitination at Lys119 (H2Aub) and plays a crucial role in the epigenetic regulation of gene expression through cooperating with several transcriptional factors and chromatin-modifying enzymes. Our previous studies have confirmed that BAP1 represses SLC7A11-mediated cystine metabolism and promotes ferroptosis-dependent tumor suppression. However, how BAP1 regulates gene expression at the genome level and whether additional mechanisms are involved in the BAP1 regulation of ferroptosis remain unclear. Here, we integrate multi-omics analyses to explore the effects of BAP1-mediated H2Aub deubiquitination on the regulation of chromatin accessibility and gene transcription. Notably, we identified a novel target gene, ACSL4, which is positively regulated by BAP1 and contributes to BAP1-mediated ferroptosis. Importantly, genetic knockout or pharmacological inhibition of ACSL4 prevents the upregulation of lipid biosynthesis and ferroptotic cell death caused by BAP1. In addition, we demonstrated that BAP1-mediated regulation of gene expression and ferroptosis is dependent on ASXL family members instead of other BAP1-associated factors like FOXK1/2, HCFC1, and OGT. Together, our findings uncover a previously unappreciated epigenetic mechanism underlying the regulation of ACSL4 by H2A monoubiquitination, which connects ACSL4-mediated lipid metabolism to ferroptosis driven by BAP1, providing new insights into the understanding of metabolic regulation of BAP1-related diseases such as cancers.
研究领域:
癌症生物学
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表观遗传学
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细胞死亡
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代谢
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2025
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IF 16
Yuhong Xiao,Yizhe He,Da Zhong,Bo Liu,ZhiBo Tang,Xiaoyong Lan,YiYang Dong,Huixian Du,Yu Liu,Jun Luo
The presence of a neurogenic bladder is a severe but common complication of spinal cord injury (SCI). Multiple pathological factors, such as hypoxia, ischemia, and oxidative stress caused by SCI, promote M1 microglial polarization and the release of proinflammatory factors to amplify inflammation. An excessive inflammatory response stimulates the generation of reactive oxygen species (ROS) and induces oxidative stress to promote neuronal ferroptosis, thus leading to bladder dysfunction after SCI. Therefore, promoting the recovery of neural function by regulating the interaction between microglia and neurons is important. For this purpose, we developed an engineered immunoregulatory cyanobacterial capsule named siRNA@Cyanzyme, which consists of MnO2@zeolitic-imidazolate framework@cyanobacteria (Cyanzyme) and a small-interfering RNA targeting ACSL4 (siRNA-ACSL4). Cyanzyme reversed M1 microglial polarization via photosynthetic oxygen to promote anti-inflammatory factor release. MnO2 nanoenzymes grown on the surface of ZIF-8 eliminated excessive ROS to reduce oxidative stress. Moreover, Cyanzyme increased the delivery efficiency of siRNA-ACSL4, which is a key regulator of ferroptosis. Both treatments alleviated GABAergic neuron damage to mitigate bladder dysfunction. Our data demonstrated that siRNA@Cyanzyme effectively reversed M1 microglial polarization, reduced neuronal ferroptosis, and ultimately restored neurogenic bladder function.
研究领域:
医学
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神经科学
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生物工程
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DOI
PubMed
高影响因子
Journal of Orthopaedic Surgery and Research
·
2023
·Vol. 18
·期 1
·1-15
·
IF 2.6
Xue Xiang,Dai Tianming,Chen Junyan,Xu Yangyang,Yang Zhenyu,Huang Jian,Xu Wuyan,Li Siming,Meng Qingqi
Background Osteoarthritis (OA) is a prevalent disease plaguing the elderly. Recently, chondrocyte ferroptosis has been demonstrated to promote the progression of OA. Peroxisome proliferator-activated receptor-γ (PPARγ) is an important factor in maintaining cartilage health. However, the relationship between PPARγ and chondrocyte ferroptosis in OA and its mechanism is completely unclear.Methods We established a surgically induced knee OA rat model to investigate PPARγ and chondrocyte ferroptosis in OA. Rat knee specimens were collected for Safranin O/Fast Green staining and immunohistochemical staining after administered orally placebo or pioglitazone (PPARγ agonist) for 4 weeks. We used RSL3 to establish a chondrocyte ferroptosis model cultured in vitro to study the role of PPARγ activation toward ferroptosis, mitochondrial function, and PTEN-induced putative kinase 1 (Pink1)/Parkin-dependent mitophagy. GW9662 (PPARγ antagonist), Mdivi-1 (mitophagy inhibitor), and chloroquine (mitophagy inhibitor) were employed to investigate the mechanism of PPARγ-Pink1/Parkin-dependent mitophagy in the inhibition of ferroptosis.Results We found that PPARγ activation by pioglitazone attenuated not only OA but also inhibited the expression of the ferroptosis marker acyl-CoA synthetase long-chain family member 4 (ACSL4) at the same time in rats. Furthermore, in vivo and in vitro data indicated that PPARγ activation restored Pink1/Parkin-dependent mitophagy, improved mitochondrial function, inhibited chondrocyte ferroptosis, and delayed the progression of OA.Conclusion sThe present study demonstrated that PPARγ activation attenuates OA by inhibiting chondrocyte ferroptosis, and this chondroprotective effect was achieved by promoting the Pink1/Parkin-dependent mitophagy pathway.
研究领域:
骨科
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Cells
·
2026
·Vol. 15
·期 18
·1657
·
IF 6
Ting Li,Wenting Yu,Huanzhi Wan,Xuan Yu,Xi Lian,Ziqi Zhou,Shimin Zong,Hongjun Xiao
Cisplatin–induced ototoxicity is a significant clinical issue linked to ferroptosis and mitophagy dysfunction. This study investigated how mitophagy regulates ferroptosis in cisplatin–induced hearing loss using cultured primary rat cochlear marginal cells in vitro and a C57BL/6J mouse model of cisplatin–induced ototoxicity in vivo. Cisplatin suppressed the PTEN–induced putative kinase 1 (PINK1) pathway, impaired mitophagy, and triggered ferroptosis characterized by iron overload, lipid peroxidation, increased acyl–CoA synthetase long–chain family member 4 (ACSL4), and decreased glutathione peroxidase 4. Pharmacological activation of mitophagy or PINK1 overexpression alleviated ferroptosis in vitro, while deferoxamine treatment reduced cisplatin–induced hearing loss and blood–labyrinth barrier damage in vivo. Mechanistically, restoration of mitophagy was associated with increased mitochondrial targeting and reduced cytosolic accumulation of ACSL4, potentially through mitophagic clearance, thereby suppressing ferroptosis. These findings support a model in which impaired PINK1–associated mitophagy contributes to cytosolic ACSL4 accumulation and ferroptotic injury. Modulating mitophagy and ACSL4 subcellular distribution may represent a potential strategy for mitigating cisplatin–induced ototoxicity.
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DOI
高影响因子
IBRO Neuroscience Reports
·
2024
·
IF 2
Min Wei,Yi Liu,Dongsheng Li,Xingdong Wang,Xiaodong Wang,Yuping Li,Zhengcun Yan,Hengzhu Zhang
Background Following recent research advancements, an increasing level of evidence had been published to indicate that celastrol exerted a therapeutic effect on a range of nervous system diseases. This study therefore aimed to investigate the potential involvement of celastrol on ferroptosis and the blood-brain barrier disruption in intracerebral haemorrhage. Methods We established a rat intracerebral haemorrhage and adrenal pheochromocytoma cell (PC12) OxyHb models using an ACSL4 overexpression vector. Ferroptosis-related indices were assessed using corresponding assay kits, and immunofluorescence and flow cytometry were used to measure reactive oxygen species (ROS) levels. Additionally, quantitative PCR (qPCR) and western blot analyses were conducted to evaluate the expression of key proteins and elucidate the role of celastrol in intracerebral haemorrhage (ICH). Results Celastrol significantly improved neurological function scores, blood-brain barrier integrity, and brain water content in rats with ICH. Moreover, subsequent analysis of ferroptosis-related markers, such as Fe2+, ROS, MDA, and SOD, suggested that celastrol exerted a protective effect against the oxidative damage induced by ferroptosis in ICH rats and cells. Furthermore, Western blotting indicated that celastrol attenuated ferroptosis by modulating the expression levels of key proteins, including acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), and anti-transferrin receptor 1 (TFR1) both in vitro and in vivo. ACSL4 overexpression attenuated the neuroprotective effects of celastrol on ICH in vitro. Molecular docking analysis revealed that celastrol interacted with ACSL4 via the GLU107, GLN109, ASN111, and LYS357 binding sites. Conclusions Celastrol exerted antioxidant properties and aids in neurological recovery after stroke by suppressing ACSL4 expression during ferroptosis. As such, this drug represented a promising pharmaceutical candidate for the treatment of ICH.
研究领域:
神经科学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
RESPIRATORY RESEARCH
·
2026
·
IF 5.7
Yi Yanjun,Hu Yidu,Ren Shencheng,Wu Yingting,Chen Xinran,Lu Yang,Yu Qi,Zuo Di,Bi Guoshu,Wang Qun,Zhan Cheng,Bian Yunyi
Background KRAS G12C-targeted therapies have transformed the treatment of KRAS G12C-mutant lung adenocarcinoma. However, acquired resistance to these therapies, whose underlying molecular mechanisms are not fully understood, presents a major obstacle to achieving long-term therapeutic success. The purpose of this study was to elucidate the mechanisms of acquired resistance to KRAS G12C inhibitors and identify potential regulators of resistance in lung adenocarcinoma. Methods Two lung adenocarcinoma cell lines (H23 and H2122) were exposed to escalating doses of two novel KRAS G12C inhibitors, fulzerasib and garsorasib, to generate resistant variants. Transcriptomic profiling was conducted to identify genes consistently upregulated in resistant cells. CRISPR/Cas9-mediated knockout (MXD4-KO) and siRNA-mediated knockdown of MXD4 were performed to assess its role in drug resistance. Mechanistic investigations employed inhibitors of ferroptosis, apoptosis, and necrosis, along with assays measuring lipid peroxidation and malondialdehyde levels. Further analysis included ferroptosis-related gene expression profiling, lipidomic profiling, ChIP-Seq, ChIP-qPCR, and dual-luciferase reporter assays. The findings were validated in patient-derived organoids (PDOs) and nude mouse models. Results Transcriptomic profiling identified 11 genes consistently upregulated in resistant cells, with MXD4 emerging as a key resistance regulator. CRISPR/Cas9-mediated knockout of MXD4 restored sensitivity to fulzerasib, garsorasib, sotorasib, and adagrasib, an effect fully reversed upon MXD4 re-overexpression. Similarly, siRNA-mediated knockdown of MXD4 in resistant cells restored drug sensitivity. Mechanistic studies revealed that MXD4 specifically suppresses ferroptosis, rather than apoptotic or necrotic pathways, by repressing ACSL4 expression and blocking its catalytic synthesis of phosphatidylethanolamine-polyunsaturated fatty acids (PE-PUFAs). ACSL4 knockout or overexpression abolished MXD4’s ability to promote ferroptosis suppression and resistance to KRAS G12C inhibitors. ChIP-Seq, ChIP-qPCR, and dual-luciferase reporter assays confirmed that MXD4 directly binds to and represses the ACSL4 promoter. These findings were validated in PDOs and nude mouse models, where MXD4 knockout restored therapeutic sensitivity, while ACSL4 knockout blocked MXD4’s resistance-promoting effects. Conclusions This study uncovers a novel resistance mechanism in which MXD4 transcriptionally silences ACSL4 to suppress ferroptosis, enabling cancer cells to evade KRAS G12C inhibitors. Targeting the MXD4-ACSL4 axis represents a promising strategy to overcome therapeutic resistance in KRAS G12C-mutant lung cancer, potentially improving long-term treatment outcomes.
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DOI
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2026
·
IF 8
Baisheng Sun,Lingxin Liu,He Zhang,Xiaoli Wang,Lanlan Chen,Yan Shen,Hui Liu,Hongjun Kang,Feihu Zhou
Post-traumatic septic myocardial dysfunction (PT-SIMD) is a life-threatening condition with high mortality and no specific treatment. Ferroptosis, an iron-dependent regulated cell death pathway driven by lipid peroxidation, has been implicated in septic cardiac injury, yet the endogenous mechanisms that counteract this process remain poorly understood. We aimed to identify novel cardioprotective regulators of ferroptosis in PT-SIMD using unbiased proteomics and to investigate whether the GLP-1 receptor agonist semaglutide (SEMA) confers protection through modulation of mitochondrial E3 ubiquitin ligases. In a rat model combining limb crush injury and cecal ligation and puncture (CLP), PT-SIMD was accompanied by marked myocardial ferroptosis, evidenced by elevated ACSL4, reduced GPX4/FSP1, and 4-HNE accumulation. Quantitative 4D-DIA proteomic profiling identified March5, a mitochondrial E3 ubiquitin ligase, as significantly downregulated. In primary neonatal rat ventricular myocytes, LPS exposure suppressed March5 expression in a dose- and time-dependent manner. Knockdown of March5 using siRNA exacerbated LPS-induced ferroptosis, increasing ACSL4 protein levels, labile Fe2+, and lipid peroxidation. Notably, SEMA treatment upregulated March5 expression, attenuated ACSL4 accumulation, and ameliorated ferroptotic injury. Crucially, siRNA-mediated silencing of March5 in cardiomyocytes completely abolished the anti-ferroptotic and cytoprotective effects of SEMA. Collectively, March5 functions as a critical endogenous suppressor of ferroptosis in PT-SIMD by negatively regulating ACSL4. Semaglutide exerts its cardioprotective action via March5-dependent inhibition of the ACSL4 ferroptosis axis, highlighting a promising therapeutic strategy for sepsis-associated myocardial dysfunction.
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DOI
高影响因子
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