Unveiling a novel pathway: Ginseng vanillic acid fights heart failure by coupling mitophagy to pyroptosis through the PINK1-BRCA1-NLRP3 axis.

BACKGROUND: Heart failure (HF) represents a frequent and serious complication of hypertensive diseases. Substantial evidence has implicated angiotensin II (Ang II) in the promotion of cardiac remodeling and inflammation associated with hypertension. Vanillic acid (VA), an organic acid derived from natural sources such as ginseng, demonstrates a spectrum of bioactivities including anti-inflammatory and antioxidant effects. PURPOSE: This study aimed to elucidate the potential of VA in attenuating Ang II-induced HF and to delineate its underlying mechanism of action. METHODS: In C57BL/6 mice, HF was induced by 4-week Ang II infusion. To delineate the cardioprotective mechanisms of VA, mice were treated with VA orally for 2 weeks following the initial 2 weeks of Ang II exposure, with subsequent cardiac RNA sequencing. VA-binding proteins were validated by molecular docking, DARTS, CETSA, and SPR. RESULTS: VA significantly ameliorated cardiac dysfunction without affecting blood pressure, concurrently suppressing cardiac fibrosis, hypertrophy, and inflammation. RNA sequencing implicated the PINK1 pathway, which was supported by in vitro observations of improved mitochondrial morphology and autophagic flux in NRVMs. Furthermore, direct binding between VA and BRCA1 was confirmed by molecular docking, DARTS, CETSA, and SPR. CONCLUSIONS: This study demonstrates that VA suppresses NLRP3 inflammasome-mediated heart failure by restoring cardiomyocyte mitochondrial function through the PINK1- BRCA1 signaling axis. These findings identify VA as a promising therapeutic candidate for HF and support its further development as a novel agent targeting mitophagy and metabolic recovery in the stressed heart.