Stabilisation of PRCP by deubiquitinase‐targeting chimera (DUBTAC) to replenish autophagy for ameliorating pathological cardiac hypertrophy

作者：Fangchao Zhou, Jun Xia, Yingjuan Liu, Wenqi He, Hongyuan Zhang, Bernard Keavney, Min Zi, Binh Nguyen, Tamer Mohamed, Jessica M. Miller, Riham Abouleisa, Susanne Hille, Elizabeth J. Cartwright, Oliver J. Müller, Honglin Xu, Sam Butterworth, Xin Wang · 发表于：British Journal of Pharmacology · 年份：2025 · DOI：10.1111/bph.70094 · 被引用次数：6 · 研究领域：Autophagy in Disease and Therapy、Cardiac Fibrosis and Remodeling、Endoplasmic Reticulum Stress and Disease

BACKGROUND AND PURPOSE: Autophagy is essential for cellular homeostasis, and its impairment contributes to cardiac hypertrophy. Modulating autophagy has shown potential in treating pathological hypertrophy. Prolylcarboxypeptidase (PRCP), a lysosomal enzyme that hydrolyzes angiotensin II to Ang1-7, has an unclear role in cardiac autophagy and hypertrophy. This study explores PRCP's function in regulating autophagy under hypertrophic stress and its potential as a therapeutic target. EXPERIMENTAL APPROACH: ) mice were generated using CRISPR/Cas9, while PRCP was overexpressed in the heart using adeno-associated virus 9. Cardiac function was evaluated via echocardiography and histological analysis. Autophagy markers were assessed by immunostaining, electron microscopy, and protein expression. In vitro, PRCP expression was manipulated in H9c2 cells. A novel DUBTAC compound was also synthesized to stabilize PRCP, and its protective effects were tested in H9c2 cells and hESC-derived cardiomyocytes under isoprenaline-induced stress. KEY RESULTS: mice developed more severe cardiac hypertrophy, fibrosis, and diastolic dysfunction after TAC. These mice showed reduced autophagosome formation and decreased expression of autophagy-related proteins WDR1 and WIPI1. In contrast, PRCP overexpression mitigated hypertrophy and preserved autophagy. Mechanistically, PRCP regulated autophagy via the interaction of WDR1 with WIPI1. Stabilizing PRCP with DUBTAC prevented its degradation and maintained...