Gentianella acuta-derived Gen-miR-5 regulates HDAC6 lactylation by targeting PFKP/YAP/p300 axis to attenuate cardiac hypertrophy

Impairment of cardiomyocyte mitochondrial function caused by pressure overload is a central event in the development of cardiac hypertrophy (CH). Gentianella acuta Hulten, widely consumed as an herbal tea alternative by the Mongolian and Ewenki hunters, has demonstrated significant protective effects on cardiovascular. However, the bioactive components responsible for the medicinal efficacy of G. acuta, as well as the mechanisms underlying its anti-CH effects, remain incompletely understood. In the present study, we demonstrate that Gen-miR-5, isolated from G. acuta, effectively mitigates angiotensin Ⅱ induced CH. Mechanistically, Gen-miR-5 suppresses the sustained activation of yes-associated protein (YAP) by downregulating platelet isoform phosphofructokinase, thereby disrupting the YAP/p300/histone deacetylase 6 (HDAC6) interaction and subsequently reducing lactylation at the HDAC6 K901 site. Moreover, Gen-miR-5 curtails lactate accumulation in cardiomyocytes, further diminishing lactylation at this site. These processes collectively contribute to the alleviation of mitochondrial oxidative stress, the restoration of mitochondrial membrane potential, and the stabilization of mitochondrial dynamics, thus inhibiting myocardial hypertrophy. These findings highlight the therapeutic potential of miRNAs derived from G. acuta in treating cardiac remodeling diseases and clarify the molecular mechanisms of their cardioprotective effects.