DOI: https://doi.org/10.1016/j.taap.2026.117800
Abstract
This study aims to delineate the specific mechanism through which TGF-β mediates NaF-induced cardiotoxicity, with a focus on its regulatory role in the Wnt/β-catenin signaling pathway. We assessed NaF-induced cytotoxicity in AC16 cardiomyocytes by CCK-8, crystal violet staining, and EdU assays; determined cell cycle progression and apoptosis by flow cytometry; and systematically evaluated ROS levels, mitochondrial function, oxidative stress, inflammation, and expression using fluorescent probes, enzymatic assays, RT-qPCR, and Western Blot. The in vivo cardiotoxic mechanism of NaF was further verified in a rat model. NaF triggers cardiotoxicity in AC16 cardiomyocytes by inhibiting the Wnt/β-catenin pathway and activating TGF-β signaling, leading to suppressed proliferation, cell cycle arrest, and apoptosis. These changes further intensify oxidative stress, mitochondrial dysfunction, and inflammation. In rats, NaF exposure caused abnormal ECG patterns and cardiac tissue damage, linked to upregulated TGF-β signaling and downregulated Wnt/β-catenin activity. Corresponding molecular changes included decreased expression of antioxidant factors (NQO1, HO-1), increased levels of inflammatory mediators (IL-6, IL-8), and P16, MMP3, P53, P21. Together, these findings clarify key mechanisms of fluoride-induced cardiotoxicity and offer a theoretical basis for managing fluorosis-related cardiac injury. NaF inhibits AC16 cardiomyocyte proliferation and induces apoptosis, cell cycle arrest, oxidative stress, mitochondrial damage, and inflammatory responses. These effects are mediated through upregulation of the TGF-β signaling pathway and concurrent inhibition of the Wnt/β-catenin pathway.