Abstract
Fluoride (F), an environmental contaminant, is known to induce cardiotoxicity, although the precise molecular mechanisms remain unclear. This study aimed to investigate the role of the SIRT1/PI3K/AKT signaling pathway in F-induced cardiotoxicity and explore the potential protective effects of SIRT1 activation. Human AC16 cardiomyocytes and zebrafish embryos were exposed to increasing concentrations of sodium NaF. Cellular assays were used to assess viability, apoptosis, cell cycle distribution, and oxidative stress. Expression levels of oxidative and inflammatory markers, as well as components of the SIRT1/PI3K/AKT pathway, were analyzed by western blotting, immunofluorescence, and real-time PCR. Zebrafish were evaluated for cardiac developmental abnormalities, apoptosis, and oxidative stress. The SIRT1 agonist SRT1720 was used to evaluate the protective effects of SIRT1 activation. Statistical analysis was performed using SPSS 23 Software and GraphPad Prism7 software, with significant differences evaluated by one-way analysis of variance (ANOVA) and Dunnett's test (p < 0.05). NaF exposure significantly inhibited AC16 cell proliferation, induced G1 phase arrest, and increased apoptosis in a dose-dependent manner. Reactive oxygen species levels were elevated, accompanied by downregulation of antioxidant proteins and upregulation of inflammatory cytokines. NaF markedly suppressed SIRT1, PI3K, and AKT expression while activating FOXO1a. Zebrafish embryos exhibited dose-dependent cardiac malformations, increased apoptosis, and elevated oxidative stress markers. Treatment with SRT1720 restored SIRT1/PI3K/AKT pathway activity, enhanced cell proliferation, reduced apoptosis, and alleviated oxidative and inflammatory responses in both cell and zebrafish models. This study demonstrates that F induces cardiotoxicity by disrupting the SIRT1/PI3K/AKT signaling pathway, leading to increased oxidative stress, inflammation, and apoptosis. Activation of SIRT1 by SRT1720 mitigates these effects, highlighting the protective role of this pathway in F-related cardiac injury. These findings provide mechanistic insights and identify potential molecular targets for the prevention and treatment of fluorosis-associated cardiovascular toxicity.