TOXICOLOGY IN VITRO
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2023
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IF 3.2
Ruijun Qin,Ping Wang,Lingzhi Li
Chronic obstructive pulmonary disease (COPD), a heterogeneity of chronic respiratory disease pattern, presents considerable prevalence and mortality. We aimed to explore the role and mechanisms of Jumonji domain-containing protein-3 (JMJD3) in COPD. The viability and JMJD3 expression in human bronchial epithelial cell line BEAS-2B were respectively assayed by CCK-8 assay and Western blot following stepwise exposure to increasing concentrations of cigarette smoke extract (CSE). After JMJD3 was silenced and acyl-CoA synthetase long-chain family member 4 (ACSL4) was overexpressed in CSE-treated BEAS-2B cells, cell viability, cytotoxicity, oxidative stress and total iron level were estimated using kits. ELISA estimated inflammatory levels. DCFH-DA probe and BODIPY 581/591 C11 probe were exposed to assess ROS production and lipid peroxidation. Western blot tested the expressions of ferroptosis-associated proteins. Besides, H3K27me3 and ACSL4 expressions were tested by Western blot and immunofluorescence staining. In CSE-induced BEAS-2B cells, JMJD3 expression was increased and deletion of JMJD3 improved cell viability, reduced LDH release, mitigated inflammation, oxidative stress and inhibited ferroptosis. Moreover, JMJD3 interference raised H3K27me3 expression whereas lessened ACSL4 expression in CSE-treated BEAS-2B cells. CSE exposure reduced the abundance of ACSL4 in H3K27me3 antibody. Further ACSL4 elevation reversed the impacts of JMJD3 silencing on the damage of CSE-induced BEAS-2B cells. Collectively, JMJD3 depletion might suppress ferroptosis mediated by ACSL4 to alleviate CSE-triggered inflammation and oxidative stress in BEAS-2B cells.
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KAOHSIUNG JOURNAL OF MEDICAL SCIENCES
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2025
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IF 3.1
Rui-Shi Wei,Yong-Ping Liu,Chun-Dong Gu,Shi-Lei Zhao,Li Feng,Jian-Rong Yu
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, with a 5-year survival rate of less than 20% and a high risk of recurrence despite advances in treatment. This study aimed to identify new therapeutic targets to increase the effectiveness of NSCLC treatments. We examined the role of USP54 in ferroptosis using an MTT assay and assessed the levels of reactive oxygen species (ROS), ferrous iron (Fe 2+ ), and malondialdehyde (MDA). To explore the underlying molecular mechanism, the intermolecular interactions was assessed using coimmunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays. We found that USP54 expression was reduced in NSCLC and that its overexpression inhibited NSCLC cell proliferation while inducing ferroptosis, as indicated by increased ROS, Fe 2+ , and MDA levels, along with changes in SLC7A11, GPX4, and ACSL4 expression. Additionally, USP54 mediated the deubiquitination of FOXA2, decreasing its degradation. And FOXA2 promoted ACSL4 transcription, which further induced ferroptosis in NSCLC cells. In conclusion, USP54 promotes ferroptosis and inhibits NSCLC progression by stabilizing FOXA2, which in turn activates ACSL4 transcription. This study provides a theoretical foundation for the development of therapies targeting USP54 or ACSL4 for NSCLC treatment.
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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癌症研究
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Journal of Ovarian Research
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2025
·Vol. 19
·期 1
·8
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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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TISSUE & CELL
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2026
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IF 3.1
Mingyue Zhang,Huichong Xu,Kaiwen Sun,Shuai Zhang,Shengnan Wang,Liqi Lin,Hongyu Li,Ying Hu
Ano5 loss alleviates osteoporosis by inhibiting osteoclastogenesis in OVX mice. • Ano5 deficiency triggers osteoclast ferroptosis by upregulating ACSL4 protein. • The Ano5 -ACSL4-ferroptosis axis is a therapeutic target for osteoporosis. Osteoporosis is driven by a pathological imbalance in bone remodeling, with osteoclast hyperactivation being a primary driver of bone loss. However, the intrinsic signaling nodes that govern osteoclast survival and function remain poorly understood. While loss-of-function mutations in Anoctamin 5 ( Ano5 ) are associated with genetic skeletal disorders, its precise involvement in metabolic osteoporosis remains elusive. In this study, we utilized an Ano5 -deficient ovariectomized (OVX) mouse model to investigate the role of Ano5 in bone homeostasis. We found that genetic depletion of Ano5 significantly attenuated the osteoporotic phenotype in OVX mice, evidenced by preserved bone microarchitecture, enhanced biomechanical properties, and suppressed bone resorptive activity. Mechanistically, Ano5 -deficient osteoclasts exhibited classical hallmarks of ferroptosis, including the accumulation of the lipid peroxidation end-product malondialdehyde (MDA), elevated reactive oxygen species (ROS), and a notable upregulation of the key lipid metabolic enzyme ACSL4 at the protein level. Importantly, the impaired osteoclastogenesis observed in Ano5 -deficient cells was effectively rescued by pharmacological inhibition of either ferroptosis (via Ferrostatin-1) or ACSL4 activity (via Rosiglitazone), which restored TRAP-positive osteoclast numbers, F-actin ring formation, and the expression of resorptive markers such as CTSK. Our findings identify Ano5 as a critical regulator of bone remodeling that modulates osteoclastogenesis through the ACSL4-dependent ferroptosis pathway. This study not only uncovers a previously unrecognized molecular axis in bone cell biology but also highlights the Ano5 -ACSL4-ferroptosis axis as a potential therapeutic target for the treatment of osteoporosis.
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Frontiers in Pharmacology
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2024
·
IF 4.4
Yadong Zhang,Rui Wen,Jingyi Ren,Fan Zhang,Huanting Pei,Jinshi Zuo,Yuxia Ma
Introduction: Exposure to fine particulate matter (PM2.5) is known to be associated with cardiovascular diseases. Sesamin (Ses) is a natural phenolic compound found in sesame seeds and sesame oil. Ferroptosis is a novel mode of cell death characterised by iron-dependent lipid peroxidation. This study aims to explore whether PM2.5 can induce ferroptosis in H9C2 cells and to investigate the precise protective mechanism of Ses.Methods: Based on transcriptomic data, PM2.5 may induce ferroptosis in cardiomyocytes. The ferroptosis inducer erastin and ferroptosis inhibitor ferrostatin-1 (Fer-1) were used to illustrate the mechanisms involved in PM2.5-induced H9C2 cell injury. Using network pharmacology, the pharmacological mechanism and potential therapy targets of Ses were explored for the treatment of PM2.5-induced cardiomyocyte injury. H9C2 cells were cultured and pretreated with Fer-1 or different concentrations of Ses, and then cardiomyocyte injury model was established using erastin or PM2.5. Indicators of oxidative responses, including total superoxide dismutase, reduced glutathione, glutathione peroxidase and malondialdehyde, were measured. The expression levels of ferroptosis-related proteins were determined through Western blot analysis.Results: Results demonstrate that PM2.5 induces ferroptosis in H9C2 cells and Ses exerts a protective effect by suppressing ACSL4-mediated ferroptosis.Discussion: Overall, these findings elucidate a novel mechanism by which Ses ameliorates the detrimental effects of PM2.5 on cardiomyocytes.
研究领域:
心血管疾病
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药理学
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毒理学
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分子生物学
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AQUACULTURE
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2026
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IF 3.9
Yi-Ran Zhao,Tong-Hao Wang,Ze-Xin Zhao,Xiao-Tian Niu,Hong-Ming Lv,Yan-Bing Li,Yang Cao,Mu-Yang Li
In the present study, we evaluated the effects of deoxynivalenol (DON) on intestinal oxidative stress, immunity, ferroptosis, and endoplasmic reticulum stress in Channa argus . Furthermore, we investigated the mechanism underlying DON-induced cytotoxicity by inhibiting ACSL4 in macrophages. In vivo analysis demonstrated DON inhibits growth and even leading to increased mortality. DON induces intestinal ROS and iron ion accumulation, thereby causing endoplasmic reticulum dysfunction and triggering oxidative stress and ferroptosis. This process is accompanied by decreased levels of ferroptosis-inhibiting proteins (GPX4, FPN1, and FSP1), along with increased ACSL4 and ROS levels. Furthermore, DON-induced ROS accumulation elicits endoplasmic reticulum dysfunction and drives the progression of immunosuppression and inflammation. In vitro analysis demonstrated that inhibition of ACSL4 affects macrophage activity as well as ROS and ATP levels, representing a potential intervention strategy to restore immune cell function. This study demonstrates that targeting ACSL4 may serve as a potential strategy for alleviating DON-mediated intestinal injury in C. argus .
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FREE RADICAL BIOLOGY AND MEDICINE
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2022
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IF 8.101
Shuhui Liu,Zhangshan Gao,Wanqiu He,Yuting Wu,Jiwen Liu,Shuo Zhang,Liping Yan,Shengyong Mao,Xizhi Shi,Wentao Fan,Suquan Song
Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most common chronic liver disorders in the world, and yet has no approved pharmacotherapy due to the etiology is complex. In the last ten years, increasing evidence have identified the environmental pollutants as risk factors for MAFLD. However, the underlying mechanism remains unclear. Our study found that bromoacetic acid (BAA, a typical kind of environmental toxin) increased triglycerides and total cholesterol levels as well as induced obvious hepatic steatosis and inflammation. The lipidomics showed that ferroptosis was implicated in the environmental toxin–linked MAFLD. Besides, the analysis of microbial metabolomics showed significant change of gut microbiome in BAA groups and the content of gut microbiota metabolite (glycochenodeoxycholate, GCDCA) increased sharply. In vitro study, we observed features of ferroptotic cells by transmission electron microscopy after BAA/GCDCA treatment . Besides, we demonstrated that BAA/GCDCA significantly increased iron contents, with upregulating transferrin receptor (TFR) and acyl-CoA synthetase long-chain family 4 (ACSL4) expression levels. By contrast, iron chelator or silencing TFR relieved BAA/GCDCA-induced lipid metabolism disorder and inflammation. What's more, the interaction between TFR and ACSL4 was also identified. Taken together, we found that, in response to environmental toxin , gut microbiota metabolite GCDCA activates TFR-ACSL4-mediated ferroptosis, which triggered subsequent lipid metabolism disorder and inflammation. Moreover, these findings firstly highlighted the functional relevance among ferroptosis, lipid metabolism and gut microbiota metabolite during environmental pollutant exposure, which shed light on the deep mechanism of environmental toxin-related MAFLD, providing potential targets for the prevention of MAFLD.
研究领域:
肝病学
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毒理学
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微生物学
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代谢组学
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脂质组学
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JOURNAL OF MEDICINAL CHEMISTRY
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2022
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IF 8.039
Haohao Wang,Di Wu,Chunyu Gao,Hongbo Teng,Yan Zhao,Zhongmei He,Weijia Chen,Ying Zong,Rui Du
In this study, 70 new seco-lupane triterpene derivatives were designed, synthesized, and characterized, and their in vitro anticancer activities were evaluated. Structure–activity relationship studies showed that most compounds inhibited the growth of a variety of tumor cells in vitro. With the extension of alkyl chains, the activity of azole compounds gradually increased while that of indole compounds first increased and then decreased. Moreover, all indole derivatives showed stronger anticancer activity than azole derivatives. In addition, compound 21 showed the strongest inhibitory effect on HepG2 cells with an IC50 value of 0.97 μM. Mechanistic studies showed that compound 21 coregulates the cell death process by inducing ferroptosis and regulating the cell cycle. In conclusion, compound 21 can be used as a ferroptosis inducer and cycle blocker to regulate the HepG2 death process, and it has the potential to become an effective new drug for the treatment of hepatocellular carcinoma.
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MedComm
·
2024
·Vol. 5
·期 12
·e70033
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IF 10.7
Jing Li,Mimi Chen,Dingwen Huang,Ziyin Li,Yu Chen,Jinhua Huang,Yuanqun Chen,Zhili Zhou,Zhiying Yu
Ovarian cancer (OV) ranks among the deadliest gynecological cancer, known for its high risk of relapse and metastasis, and a general resistance to conventional platinum‐based chemotherapy. Selenoprotein I (SELENOI) is a crucial mediator implicated in human hereditary spastic paraplegia. However, its role in human tumors remains poorly elucidated. Here, we comprehensively analyzed SELENOI expression patterns, functions, and clinical implications across various malignancies through the integration of bulk transcriptomics, cancer databases, and in vitro and in vivo experiments. Pan‐cancer analysis indicated upregulated SELENOI expression across various cancers, correlating with augmented malignancy, suppressed tumor immunity and poor prognosis. Knockdown of SELENOI caused G0/G1‐phase cell cycle arrest and diminished aggressive cancer phenotypes in OV cells. Moreover, SELENOI inhibition augments ferroptosis and reverses the cisplatin resistance in OV cells by modulating Akt phosphorylation. Conversely, overexpression of SELENOI in OV cells enhanced therapeutic sensitivity to cisplatin by upregulating Akt phosphorylation. Importantly, in vivo studies demonstrated that SELENOI inhibition suppressed ovarian tumor growth and enhanced cisplatin's anticancer effects. These findings highlight the significant role of SELENOI in OV by modulating ferroptosis and chemotherapy resistance. Targeting SELENOI represents a promising therapeutic approach to promote the efficacy of platinum‐based chemotherapy in OV, particularly in cases of resistance. Graphic summary of targeting SELENOI for promoting ferroptosis and reversing chemoresistance in ovarian cancer. Inhibition of SELENOI activated unsaturated fatty acid synthesis and impaired Akt phosphorylation, resulting in the upregulation of ACSL4 expression and induction of ferroptosis. Reduced Akt phosphorylation also led to the downregulation of ALDH3A1 expression, a key gene associated with cisplatin‐resistance, thereby enhancing cisplatin cytotoxicity in SELENOI‐silenced ovarian cancer cells.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
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转化医学
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2022
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IF 3.322
Ting Zhou,Bao Yang
Prenylated resveratrols are drug candidates presented in many natural sources. They possess multiple pharmacological activities. Due to the limited abundance in nature and disadvantage of chemical synthesis, it is required to produce prenylated resveratrols by biological strategy. In this work, a prenyltransferase iacE from Pestalotiopsis fici was prepared by heterologous overexpression. It could catalyze 2- C -prenylation of resveratrol efficiently. Dimethylallyl diphosphate (DMAPP) and geranyl diphosphate (GPP) could serve as prenyl donor. Glu97, Thr114 and Tyr413 were proved to be important residues in the active site by site-directed mutagenesis. The product was purified and identified to be 2- C -prenyl resveratrol by NMR . 2- C -prenyl resveratrol exerted neuroprotective activity through inhibiting ROS overproduction and improving the activities of antioxidant enzymes in HT22 cell. The genes involved in antioxidant defense were regulated, including upregulated CAT , SOD2 , NFE2L2 , GPx4 , and downregulated PTGS2 and ACSL4 . These results supplied a novel technique for prenylated resveratrols production.
研究领域:
生物技术
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药理学
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神经科学
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Frontiers in Oncology
·
2025
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IF 3.3
Jing Cheng,Zhihan Liu,Haibo Liu,Chao Fang,Jun Li
Colorectal cancer (CRC) is one of the most prevalent malignant tumors worldwide, with its pathogenesis tightly linked to the regulation of cell death. Ferroptosis plays a pivotal role in the initiation, progression, and treatment of CRC. In our previous studies, we demonstrated that PPP2CA knockdown enhances the malignant phenotype of CRC cells while increasing their susceptibility to ferroptosis, albeit this latter effect frequently mitigates the malignant phenotype. The present study aims to further elucidate the regulatory mechanism underlying the association between PPP2CA and ferroptosis. Lentiviral-mediated PPP2CA knockdown was performed in CRC cell lines HCT116 and SW480 to establish stable PPP2CA-knockdown models, and PPP2CA gene expression in these models was verified. Colony formation assays and scratch wound healing assays were used to assess the proliferative and migratory capacities of CRC cells after PPP2CA knockdown. Additionally, CRC samples from The Cancer Genome Atlas (TCGA) database were analyzed via bioinformatics approaches to identify ferroptosis-related genes closely correlated with PPP2CA, with subsequent validation in model cells. The STRING database was employed to analyze the interaction networks between PPP2CA and target ferroptosis-related genes, predict potential signaling pathways via which PPP2CA regulates cellular ferroptosis, and validate these findings in model cells. Compared with the control group, HCT116 and SW480 cells in the PPP2CA-knockdown group exhibited significantly enhanced proliferative and migratory capacities. Bioinformatics analysis identified the top 10 most significant ferroptosis-related genes associated with PPP2CA. Validation in model cells showed that the expression levels of transferrin receptor (TFRC) and acyl-CoA synthetase long-chain family member 4 (ACSL4) were significantly upregulated. STRING analysis and in-model-cell validation indicated that increased mTOR phosphorylation subsequent to PPP2CA knockdown could upregulate the protein expression levels of transferrin receptor (TfR, encoded by the TFRC gene) and ACSL4, and this effect could be reversed by the mTOR inhibitor rapamycin. Thus, PPP2CA knockdown enhances the malignant phenotype of CRC cells, while potentially upregulating the expression of ferroptosis-related genes TFRC and ACSL4 via the mTOR signaling pathway, thereby increasing ferroptosis sensitivity.
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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癌症研究
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信号转导
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PHYTOMEDICINE
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2026
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IF 11.3
Minghui Zhao,Hongfang Mu,Qian Ji,Jiale Song,Fuyixuan Zheng,Tianlong Liu,Wenbin Li,Rong Wang
Background The effects of persistent hypoxic conditions in high-altitude regions on metabolic disorders remain poorly understood and in-depth investigation into its underlying molecular mechanisms is notably insufficient. As a metabolism-associated liver disease, the pathogenesis of non-alcoholic fatty liver disease (NAFLD) under hypoxic conditions urgently requires clarification. Previous studies have demonstrated that resveratrol (Rsv) possesses significant anti-inflammatory, antioxidant, and lipid metabolism-modulating properties, and it can act as an inhibitor of ferroptosis. Yet its precise therapeutic efficacy and mechanism in hypoxic NAFLD remain to be further explored. Objective This study aims to explore the potential mechanism by which Rsv improves the deterioration of NAFLD under hypoxia exposure. Methods Herein, we performed concurrent interventions in both in vivo and in vitro models of NAFLD, comprehensively detecting biochemical indicators (inflammatory factors, oxidative stress markers, liver function), liver histopathological changes, and nucleic acid levels to assess the effects of Rsv. By introducing ferroptosis modulators, we measured core ferroptosis parameters (mitochondrial ultrastructure, Fe²⁺, 4-HNE, LPO levels, and key protein expressions) to define disease progression patterns. By HIF-1α silencing was employed to verify its regulatory roles in ferroptosis-related factors and NAFLD pathogenesis. Co-Immunoprecipitation assays and immunofluorescence co-localization were used to explore protein interactions among ACSL4, TfR1, and HIF-1α. Conclusion Our results demonstrated that high-altitude hypoxia exacerbates NAFLD via inducing ferroptosis; HIF-1α upregulates the expression of key ferroptosis mediators (ACSL4, TfR1), and HIF-1α silencing attenuates ferroptosis. Rsv exerts therapeutic effects against hypoxia-related NAFLD by targeting the HIF-1α-mediated ferroptosis pathway. This study elucidates the pivotal role of HIF-1α-dependent ferroptosis in hypoxia-aggravated NAFLD, identifies the therapeutic targets and mechanisms of Rsv, and provides novel theoretical foundations and potential intervention strategies for clinical management of hypoxia-related NAFLD in high-altitude areas.
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