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<p>Purpose Chemotherapeutic agents, though highly effective in eliminating tumor cells, frequently cause varying degrees of myocardial injury. Doxorubicin (DOX) is a leading extensively used anthracycline-based chemotherapy agents. The present research sought to explore the role of lncRNA FAF in chemotherapy-induced cardiotoxicity and to elucidate its regulatory function via the NLRP3-Caspase-1 axis. Methods A rat model of DOX-induced cardiac toxicity was generated by administering the drug intraperitoneally, and cardiac function in rats was subsequently evaluated by echocardiography. We assessed morphological changes in rat myocardial tissue by hematoxylin-eosin and Masson staining, and measured the expression of biomarkers associated with cardiac damage, including LDH and CK-MB, using ELISA. Proteins involved in pyroptosis (GSDMD, NLRP3, and C-Caspase-1) were evaluated through TUNEL assay, immunohistochemical staining, and Western blot experiments. Cell viability was determined using the CCK-8 assay, while pyroptosis was inspected by flow cytometry, and lncRNA FAF expression was quantified by qRT-PCR. Results DOX administration induced cardiac dysfunction, myocardial tissue structural disorders and fibrosis, as well as heightened serum concentrations of LDH and CK-MB. In both animal and cell-based experiments, DOX treatment led to a decrease in lncRNA FAF expression in cardiac myocytes, accompanied by a significantly up-regulation of NLRP3, C-Caspase-1, and GSDND-N, thereby promoting cardiomyocyte pyroptosis. In contrast, high expression of lncRNA FAF enhanced cardiac myocytes viability, inhibited pyroptosis, and down-regulated the expression of NLRP3, C-Caspase-1, and GSDND-N. Importantly, these effects were reversed by treatment with the NLRP3 agonist nigericin or the pyroptosis agonist polyphyllin VI in cardiomyocytes treated with lncRNA FAF overexpression. Conclusion lncRNA FAF alleviates DOX-induced cardiomyocyte injury by enhancing cardiomyocyte viability and suppressing pyroptosis by targeting the NLRP3-Caspase-1 axis. </p>

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Involvement of LncRNA FAF in chemotherapy-induced cardiotoxicity by mediating pyroptosis through modulation of the NLRP3-Caspase-1 signaling pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月12日

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  • Ziyu Feng,
  • Jinhui Sun,
  • Qiang Geng,
  • Bichen He,
  • Jingjing Zhang,
  • Yiheshan Ainiwaer,
  • Bing Zhang,
  • Yuanming Zhang

摘要

Purpose Chemotherapeutic agents, though highly effective in eliminating tumor cells, frequently cause varying degrees of myocardial injury. Doxorubicin (DOX) is a leading extensively used anthracycline-based chemotherapy agents. The present research sought to explore the role of lncRNA FAF in chemotherapy-induced cardiotoxicity and to elucidate its regulatory function via the NLRP3-Caspase-1 axis. Methods A rat model of DOX-induced cardiac toxicity was generated by administering the drug intraperitoneally, and cardiac function in rats was subsequently evaluated by echocardiography. We assessed morphological changes in rat myocardial tissue by hematoxylin-eosin and Masson staining, and measured the expression of biomarkers associated with cardiac damage, including LDH and CK-MB, using ELISA. Proteins involved in pyroptosis (GSDMD, NLRP3, and C-Caspase-1) were evaluated through TUNEL assay, immunohistochemical staining, and Western blot experiments. Cell viability was determined using the CCK-8 assay, while pyroptosis was inspected by flow cytometry, and lncRNA FAF expression was quantified by qRT-PCR. Results DOX administration induced cardiac dysfunction, myocardial tissue structural disorders and fibrosis, as well as heightened serum concentrations of LDH and CK-MB. In both animal and cell-based experiments, DOX treatment led to a decrease in lncRNA FAF expression in cardiac myocytes, accompanied by a significantly up-regulation of NLRP3, C-Caspase-1, and GSDND-N, thereby promoting cardiomyocyte pyroptosis. In contrast, high expression of lncRNA FAF enhanced cardiac myocytes viability, inhibited pyroptosis, and down-regulated the expression of NLRP3, C-Caspase-1, and GSDND-N. Importantly, these effects were reversed by treatment with the NLRP3 agonist nigericin or the pyroptosis agonist polyphyllin VI in cardiomyocytes treated with lncRNA FAF overexpression. Conclusion lncRNA FAF alleviates DOX-induced cardiomyocyte injury by enhancing cardiomyocyte viability and suppressing pyroptosis by targeting the NLRP3-Caspase-1 axis.