Gen-miR-5 Derived from Gentianella acuta Inhibits PFKP to Prevent Fibroblast Activation and Alleviate Myocardial Fibrosis

Hongyao Ge¹Zhenyu Du^2,3Weizhe Liu^2,3,4LeTian Wang⁵Junyang Li³Gaoshan Yang^2,3,4*Aiying Li^2,3,4*

• ¹Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
• ²Hebei key laboratory of Chinese Medicine Research on Cardio-Cerebrovascular disease, Shijiazhuang, Hebei Province, China
• ³Hebei University of Chinese Medicine, Shijiazhuang, China
• ⁴Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, China
• ⁵Department of Cardiology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, Shanghai Municipality, China

Gentianella acuta (G.acuta) is widely used by Mongolian and Ewenki hunters due to its cardiovascular protective properties. Myocardial fibrosis (MF) is a critical pathological change associated with heart failure, and lactate, a byproduct of glycolysis, is a key factor involved in the progression of MF. In this study, we identified six novel specific miRNAs, which were demonstrated to be effective in treating cardiac remodeling. Among them, Gen-miR-5, derived from G.acuta, can be absorbed by mice, remain stable in cardiac tissue, and exert cross-species regulatory effects by targeting the PFKP 3' UTR. Our findings revealed that PFKP, a key rate-limiting enzyme in the glycolytic pathway, increases lactate accumulation, thereby promoting the proliferation and migration of cardiac fibroblasts (CFs) and contributing to the progression of MF.In contrast, Gen-miR-5 alleviates MF by suppressing this pathway. In conclusion, Gen-miR-5 exerts its cardioprotective effects by targeting and suppressing the expression of PFKP, a key glycolytic enzyme induced by Ang II, regulating lactate metabolism in fibroblasts, and preventing the transformation of fibroblasts into myofibroblasts, ultimately mitigating MF.