Gentiopicroside Regulates EGFR and Induces Its Lysosomal Degradation to Attenuate Heart Failure.

Abstract

Cardiac hypertrophy is a major pathological response to cardiovascular stress and a critical contributor to heart failure (HF). Gentiopicroside (GPS), a naturally occurring iridoid glycoside derived from Gentiana scabra, exhibits anti-inflammatory, antioxidant, and anti-fibrotic properties. However, its role and molecular mechanisms in cardiac hypertrophy and HF remain unclear. A pressure overload-induced cardiac remodeling model was established in C57BL/6 mice by transverse aortic constriction (TAC), followed by GPS treatment with or without the EGFR tyrosine kinase inhibitor Canertinib. Cardiac function and remodeling were evaluated by echocardiography, hemodynamic analysis, and histological staining. In vitro, neonatal rat ventricular myocytes (NRVMs) and cardiac fibroblasts (NRCFs) were used to investigate the cellular effects of GPS. EGFR knockdown, conditioned medium transfer, cellular thermal shift assay (CETSA), and lysosomal/proteasomal inhibition experiments were performed to elucidate the mechanism underlying GPS-mediated EGFR regulation. GPS markedly alleviated TAC-induced cardiac hypertrophy and fibrosis in vivo and suppressed Ang II-induced cardiomyocyte hypertrophy. GPS also reduced cardiomyocyte apoptosis and oxidative stress. Mechanistically, GPS acted as an EGFR degrader rather than a conventional kinase inhibitor, reducing total EGFR abundance without inhibiting the kinase activity of remaining receptors, thereby attenuating excessive AKT/ERK1/2 signaling. CETSA and molecular docking indicated direct GPS-EGFR interaction. GPS-induced EGFR reduction was mediated primarily through lysosomal degradation, as demonstrated by chloroquine rescue experiments, whereas proteasome inhibition had limited effects. Co-administration of Canertinib with GPS conferred no additional benefit. EGFR depletion abolished the protective effect of GPS in cardiomyocytes, indicating a cardiomyocyte-autonomous mechanism. This study identifies GPS as a regulator of EGFR stability during pathological cardiac remodeling. By promoting lysosome-dependent EGFR degradation and suppressing excessive AKT/ERK1/2 signaling, GPS attenuates cardiac hypertrophy and remodeling while preserving basal EGFR function, highlighting its potential therapeutic value for HF.