GAS6 mediates Benzo[a]pyrene-induced pathological cardiac hypertrophy via the mTOR/HIF-1α glycolytic remodeling axis.

Benzo[a]pyrene (BaP), a representative polycyclic aromatic hydrocarbon, is a pervasive environmental pollutant with emerging cardiovascular toxicity. However, the molecular mechanisms linking BaP exposure to pathological cardiac hypertrophy remain incompletely understood. Here, we integrated target-prioritization analyses with in vivo and in vitro validation to investigate whether growth arrest-specific 6 (GAS6) mediates BaP-induced cardiac remodeling. Target integration and Mendelian randomization analysis nominated GAS6 as a biologically plausible mediator associated with cardiac hypertrophy susceptibility. Structural modeling and molecular dynamics simulations further suggested a stable and structurally feasible interaction between BaP and GAS6. In a chronic BaP-exposure mouse model, BaP induced myocardial hypertrophy, myocardial fiber disorganization, and interstitial remodeling, accompanied by increased expression of GAS6, HIF-1α, VEGF-A, GLUT1, and LDHA in cardiac tissues. AAV9-mediated GAS6 silencing partially alleviated these histopathological abnormalities and reduced hypoxia- and glycolysis-associated protein expression. Consistently, in H9C2 and AC16 cardiomyocytes, BaP upregulated hypertrophic markers, including NPPA, NPPB, and MYH7, and activated mTOR/HIF-1α-associated glycolysis-related metabolic signaling. GAS6 knockdown attenuated BaP-induced hypertrophic gene expression and reduced the expression of mTOR/HIF-1α-associated glycolysis-related proteins. Collectively, these findings indicate that GAS6 contributes to BaP-induced pathological cardiac hypertrophy by linking environmental toxicant exposure to mTOR/HIF-1α-associated glycolytic remodeling. This study provides mechanistic insight into BaP-associated cardiovascular toxicity and identifies the GAS6/mTOR/HIF-1α axis as a potential mechanistic target in environmentally induced cardiac remodeling.