{"title":"ZEB1沉默通过抑制HSPA5的表达保护骨关节炎的铁下垂和线粒体功能障碍。","authors":"Jie Wan, Feng Shen, Jian Ding, Dong Ye","doi":"10.1080/08923973.2025.2520309","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Zinc finger E-box binding homeobox 1 (ZEB1), a ferroptosis-associated gene, is upregulated in osteoarthritis (OA) articular cartilage. However, whether ZEB1 regulates ferroptosis in OA progression remain unclear.</p><p><strong>Methods: </strong>ZEB1 protein levels in cartilage specimens from OA patients and normal controls were measured. Interleukin 1β (IL-1β)-induced chondrocyte injury model was established, followed by short hairpin RNA (shRNA)-mediated ZEB1 silencing in chondrocytes. Chondrocyte viability, apoptosis, inflammatory cytokine expression, extracellular matrix (ECM) degradation were assessed. Moreover, ferrous ion (Fe<sup>2+</sup>) level, reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase 4 (GPX4), mitochondrial membrane potential (MMP) and ATP level were determined. ZEB1-mediated transcriptional regulation of heat shock protein family A member 5 (HSPA5) was validated. Rescue experiments were conducted to validate the ZEB1/HSPA5 regulatory axis in chondrocyte injury. OA mouse model was constructed, and ZEB1 shRNA was injected into OA mice. The pathological changes in cartilage tissues were detected.</p><p><strong>Results: </strong>ZEB1 was upregulated in OA cartilage tissues. ZEB1 silencing attenuated IL-1β-induced apoptosis, inflammation, and ECM degradation. IL-1β treatment increased Fe<sup>2+</sup>, ROS, and MDA levels and decreased GPX4 and GSH levels in chondrocytes, while ZEB1 silencing reversed these changes. ZEB1 silencing abrogated IL-1β-induced MMP and ATP reduction. Mechanistic studies revealed that ZEB1 transcriptionally inhibited HSPA5 expression in chondrocytes. HSPA5 silencing abrogated the protective effects of ZEB1 silencing. Additionally, ZEB1 silencing alleviated articular cartilage degradation, inflammatory response, and iron deposition.</p><p><strong>Conclusion: </strong>ZEB1 silencing ameliorated IL-1β-induced chondrocyte injury and OA progression by suppressing ferroptosis and mitochondrial dysfunction via HSPA5 inhibition.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":" ","pages":"1-14"},"PeriodicalIF":2.9000,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"ZEB1 silencing protects against ferroptosis and mitochondrial dysfunction in osteoarthritis by inhibiting HSPA5 expression.\",\"authors\":\"Jie Wan, Feng Shen, Jian Ding, Dong Ye\",\"doi\":\"10.1080/08923973.2025.2520309\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Zinc finger E-box binding homeobox 1 (ZEB1), a ferroptosis-associated gene, is upregulated in osteoarthritis (OA) articular cartilage. However, whether ZEB1 regulates ferroptosis in OA progression remain unclear.</p><p><strong>Methods: </strong>ZEB1 protein levels in cartilage specimens from OA patients and normal controls were measured. Interleukin 1β (IL-1β)-induced chondrocyte injury model was established, followed by short hairpin RNA (shRNA)-mediated ZEB1 silencing in chondrocytes. Chondrocyte viability, apoptosis, inflammatory cytokine expression, extracellular matrix (ECM) degradation were assessed. Moreover, ferrous ion (Fe<sup>2+</sup>) level, reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase 4 (GPX4), mitochondrial membrane potential (MMP) and ATP level were determined. ZEB1-mediated transcriptional regulation of heat shock protein family A member 5 (HSPA5) was validated. Rescue experiments were conducted to validate the ZEB1/HSPA5 regulatory axis in chondrocyte injury. OA mouse model was constructed, and ZEB1 shRNA was injected into OA mice. The pathological changes in cartilage tissues were detected.</p><p><strong>Results: </strong>ZEB1 was upregulated in OA cartilage tissues. ZEB1 silencing attenuated IL-1β-induced apoptosis, inflammation, and ECM degradation. IL-1β treatment increased Fe<sup>2+</sup>, ROS, and MDA levels and decreased GPX4 and GSH levels in chondrocytes, while ZEB1 silencing reversed these changes. ZEB1 silencing abrogated IL-1β-induced MMP and ATP reduction. Mechanistic studies revealed that ZEB1 transcriptionally inhibited HSPA5 expression in chondrocytes. HSPA5 silencing abrogated the protective effects of ZEB1 silencing. Additionally, ZEB1 silencing alleviated articular cartilage degradation, inflammatory response, and iron deposition.</p><p><strong>Conclusion: </strong>ZEB1 silencing ameliorated IL-1β-induced chondrocyte injury and OA progression by suppressing ferroptosis and mitochondrial dysfunction via HSPA5 inhibition.</p>\",\"PeriodicalId\":13420,\"journal\":{\"name\":\"Immunopharmacology and Immunotoxicology\",\"volume\":\" \",\"pages\":\"1-14\"},\"PeriodicalIF\":2.9000,\"publicationDate\":\"2025-07-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Immunopharmacology and Immunotoxicology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/08923973.2025.2520309\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Immunopharmacology and Immunotoxicology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/08923973.2025.2520309","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
ZEB1 silencing protects against ferroptosis and mitochondrial dysfunction in osteoarthritis by inhibiting HSPA5 expression.
Background: Zinc finger E-box binding homeobox 1 (ZEB1), a ferroptosis-associated gene, is upregulated in osteoarthritis (OA) articular cartilage. However, whether ZEB1 regulates ferroptosis in OA progression remain unclear.
Methods: ZEB1 protein levels in cartilage specimens from OA patients and normal controls were measured. Interleukin 1β (IL-1β)-induced chondrocyte injury model was established, followed by short hairpin RNA (shRNA)-mediated ZEB1 silencing in chondrocytes. Chondrocyte viability, apoptosis, inflammatory cytokine expression, extracellular matrix (ECM) degradation were assessed. Moreover, ferrous ion (Fe2+) level, reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase 4 (GPX4), mitochondrial membrane potential (MMP) and ATP level were determined. ZEB1-mediated transcriptional regulation of heat shock protein family A member 5 (HSPA5) was validated. Rescue experiments were conducted to validate the ZEB1/HSPA5 regulatory axis in chondrocyte injury. OA mouse model was constructed, and ZEB1 shRNA was injected into OA mice. The pathological changes in cartilage tissues were detected.
Results: ZEB1 was upregulated in OA cartilage tissues. ZEB1 silencing attenuated IL-1β-induced apoptosis, inflammation, and ECM degradation. IL-1β treatment increased Fe2+, ROS, and MDA levels and decreased GPX4 and GSH levels in chondrocytes, while ZEB1 silencing reversed these changes. ZEB1 silencing abrogated IL-1β-induced MMP and ATP reduction. Mechanistic studies revealed that ZEB1 transcriptionally inhibited HSPA5 expression in chondrocytes. HSPA5 silencing abrogated the protective effects of ZEB1 silencing. Additionally, ZEB1 silencing alleviated articular cartilage degradation, inflammatory response, and iron deposition.
Conclusion: ZEB1 silencing ameliorated IL-1β-induced chondrocyte injury and OA progression by suppressing ferroptosis and mitochondrial dysfunction via HSPA5 inhibition.
期刊介绍：
The journal Immunopharmacology and Immunotoxicology is devoted to pre-clinical and clinical drug discovery and development targeting the immune system. Research related to the immunoregulatory effects of various compounds, including small-molecule drugs and biologics, on immunocompetent cells and immune responses, as well as the immunotoxicity exerted by xenobiotics and drugs. Only research that describe the mechanisms of specific compounds (not extracts) is of interest to the journal.
The journal will prioritise preclinical and clinical studies on immunotherapy of disorders such as chronic inflammation, allergy, autoimmunity, cancer etc. The effects of small-drugs, vaccines and biologics against central immunological targets as well as cell-based therapy, including dendritic cell therapy, T cell adoptive transfer and stem cell therapy, are topics of particular interest. Publications pointing towards potential new drug targets within the immune system or novel technology for immunopharmacological drug development are also welcome.
With an immunoscience focus on drug development, immunotherapy and toxicology, the journal will cover areas such as infection, allergy, inflammation, tumor immunology, degenerative disorders, immunodeficiencies, neurology, atherosclerosis and more.
Immunopharmacology and Immunotoxicology will accept original manuscripts, brief communications, commentaries, mini-reviews, reviews, clinical trials and clinical cases, on the condition that the results reported are based on original, clinical, or basic research that has not been published elsewhere in any journal in any language (except in abstract form relating to paper communicated to scientific meetings and symposiums).
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