Hirsutine Ameliorates High‐Fat Diet‐Induced Cardiomyopathy Through Promoting LRPPRC ‐Regulated Mitophagy via the PINK 1/Parkin Axis in Mice

ABSTRACT Hirsutine, a potent drug‐like indole alkaloid extracted from Uncaria rhynchophylla , exhibits several biological activities, including cardioprotective effects. However, the underlying regulatory mechanisms remain unclear. Herein, we aimed to examine the therapeutic effects of hirsutine on obesity‐related cardiomyopathy and investigate the potential mechanism underlying these effects. An obesity cardiomyopathy mouse model was developed by subjecting mice to a high‐fat diet (HFD) for 16 consecutive weeks, followed by an 8‐week hirsutine treatment. H9c2 cardiomyocytes treated with palmitate were utilized as an in vitro model. Invasive hemodynamic parameters and left ventricular hypertrophy indices were assessed, and the expression of related signaling molecules was analyzed using western blotting, mass spectrometry, molecular docking, RNA sequencing, immunoprecipitation, histological analysis, and transmission electron microscopy, respectively. Hirsutine significantly alleviated HFD‐induced cardiomyopathy in the mouse model. Notably, the therapeutic effect of hirsutine was reversed in Midivi‐1‐treated mice, indicating that the cardioprotective role of hirsutine is dependent on mitochondrial fission‐mediated mitophagy and Parkin. Mechanically, hirsutine maintained Parkin protein stability, and the C‐terminal region of 1103–1394 amino acids of leucine‐rich pentatricopeptide repeat‐containing protein (LRPPRC) functions as a binding motif interacting with Parkin. LRPPRC overexpression significantly enhanced Parkin protein stability, which was attenuated by deletion of the 1103–1394 amino acids of LRPPRC (LRPPRC Δ1103–1394 ). Collectively, these findings demonstrate that hirsutine ameliorates HFD‐induced cardiomyopathy by promoting Parkin protein stability through its interaction with 1103–1394 amino acids of LRPPRC. Therefore, targeting LRPPRC may represent a promising therapeutic strategy underlying the protective effects of hirsutine in HFD‐induced cardiomyopathy.