Vericiguat as a novel PPARα ligand alleviates pressure-overload-induced heart failure

Heart failure (HF) remains a critical global health challenge with limited therapeutic options. Vericiguat, a novel soluble guanylate cyclase (sGC) stimulator, has demonstrated clinical potential in HF management. This study aimed to investigate the cardioprotective effects of vericiguat and its underlying mechanism in pressure-overload-induced HF. Using a transverse aortic constriction (TAC) mouse model, we demonstrated that vericiguat significantly improved cardiac function and attenuated myocardial hypertrophy, fibrosis, and oxidative stress. In vitro, vericiguat mitigated isoproterenol (ISO)-induced hypertrophy and oxidative stress in HL-1 cardiomyocytes. RNA sequencing and pathway enrichment analysis revealed that vericiguat exerts its protective effects by modulating metabolic pathways, particularly through the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Vericiguat upregulated PPARα expression at both mRNA and protein levels, with no significant effect on PPARβ or PPARγ. CETSA and DARTS assays confirmed a direct interaction between vericiguat and PPARα, further supported by molecular docking showing stable hydrogen bonding and hydrophobic interactions, notably with residue SER280. Pharmacological inhibition of PPARα with GW6471 abolished vericiguat's protective effects, underscoring the central role of PPARα activation. In conclusion, vericiguat alleviates pressure-overload-induced HF by directly binding to, upregulating and activating PPARα, offering a novel therapeutic approach for the treatment of HF.