Huangqi–Danshen Decoction Alleviates Cardiac Fibrosis Following Myocardial Infarction by Inhibiting USP22 to Enhance the Ubiquitination of BRD4

BACKGROUND Myocardial fibrosis is a critical pathological process in the development of heart failure following myocardial infarction (MI). The Huangqi-Danshen decoction (HDD) has shown cardioprotective effects in clinical practice. Nonetheless, the precise molecular mechanisms underlying its antifibrotic effects remain to be elucidated. OBJECTIVE This study aimed to systematically investigate the therapeutic effects of HDD on myocardial fibrosis post-MI and to determine the underlying molecular mechanisms. METHODS An MI model was established in mice by ligating the left anterior descending coronary artery. Cardiac function and morphology were evaluated using echocardiography and histological analysis. In in vitro experiments, TGF-β1-stimulated human cardiac fibroblasts were treated with HDD-containing serum. The underlying mechanism of HDD was investigated using proteomic screening and molecular biology techniques. RESULTS HDD markedly improved cardiac function and attenuated myocardial fibrosis in MI mice. Proteomic analysis identified BRD4 as a key epigenetic target of HDD. HDD reduced BRD4 expression and H3K27ac levels, accompanied by decreased fibrosis-related marker expression. BRD4 overexpression or TSA treatment counteracted the inhibitory effects of HDD on H3K27ac and fibrotic markers, supporting the involvement of the BRD4/H3K27ac axis. Mechanistically, HDD promoted ubiquitin-proteasome-dependent BRD4 degradation by disrupting the interaction between BRD4 and the deubiquitinase USP22. USP22 overexpression reversed, whereas USP22 knockdown largely phenocopied, the antifibrotic effects of HDD. CONCLUSION HDD ameliorates myocardial fibrosis by targeting the USP22-BRD4 axis, promoting BRD4 degradation and inhibiting H3K27ac-mediated profibrotic transcription, offering a novel epigenetic therapeutic strategy.