Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Huangqi-Danshen Decoction Alleviates Cardiac Fibrosis Following Myocardial Infarction by Inhibiting USP22 to Enhance the Ubiquitination of BRD4.
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Hao Jiaqi, Lu Mengkai, Zhang Muxin, Lin Lin, Hu Yuanlong, Zhang Lei, Li Chao
Аннотация
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.
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.