Chlorfenapyr (CHL) is a widely used insecticide whose expanding application raises concerns about cardiotoxicity following both acute poisoning and chronic environmental exposure. The mechanisms underlying its cardiac injury remain unclear. This study investigated the role of ferroptosis and mitochondrial dysfunction in CHL-induced cardiotoxicity. Using H9c2 cardiomyocytes and a Sprague-Dawley rat model, we assessed the effects of CHL and interventions with the ferroptosis inhibitor Ferrostatin-1 (Fer-1) or the mitochondrial antioxidant MitoTEMPO. In vitro, CHL decreased cell viability and triggered mitochondrial dysfunction, mitochondrial reactive oxygen species (mtROS) burst, and downregulation of uncoupling protein 2 (UCP2). These events culminated in ferroptosis, evidenced by lipid peroxidation, GPX4 downregulation, and ACSL4 upregulation, all rescued by Fer-1 or MitoTEMPO. In vivo, CHL exposure impaired cardiac systolic function, reducing ejection fraction (EF) and fractional shortening (FS), elevated serum troponin I, and caused histopathological damage, which were ameliorated by Fer-1 or MitoTEMPO. Our findings suggest that CHL cardiotoxicity is associated with the downregulation of cardiac UCP2 expression, compromised mitochondrial redox homeostasis, and the activation of mtROS-mediated ferroptotic pathways. UCP2 and mitochondrial redox homeostasis may therefore represent candidate targets for intervention.
Zhang et al. (Fri,) studied this question.
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