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

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

  • Sci Rep. 2025 Dec 12. doi: 10.1038/s41598-025-31983-2.
Ziyu Feng # 1,  Jinhui Sun # 1,  Qiang Geng 1,  Bichen He 1,  Jingjing Zhang 1,  Yiheshan Ainiwaer 1,  Bing Zhang 2,  Yuanming Zhang 3
Affiliations

Affiliations

  • 1 Center for Anesthesia and Perioperative Medicine, The Affiliated Tumor Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, No. 789 Suzhou East Street, Urumqi, 830011, China.
  • 2 Center for Anesthesia and Perioperative Medicine, The Affiliated Tumor Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, No. 789 Suzhou East Street, Urumqi, 830011, China. [email protected].
  • 3 Office of the Party Committee (Hospital Director's Office), The Affiliated Tumor Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, No. 789 Suzhou East Street, Urumqi, 830011, China. [email protected].
  • # Contributed equally.
PMID: 41387942 DOI: 10.1038/s41598-025-31983-2
Abstract

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.

Keywords

Cardiomyocyte; Cellular pyroptosis; DOX; LncRNA FAF; NLRP3-Caspase-1 axis.

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