Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Qishen granule improves myocardial fibrosis in heart failure via Piezo1/Calpain2/LAMP1/CTSS in CCR2+ macrophages.
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Liu Jiali, Tao Meijiao, Min Shixuan, Wang Neng, Ouyang Yulin, Wen Ruijia, He Jiadi, Wang Wei, Li Chun, Zhang Yao
Аннотация
BACKGROUND: Myocardial fibrosis represents a common terminal pathological pathway in heart failure (HF), and currently, there is a lack of therapies specifically targeting the core pathological mechanisms of myocardial fibrosis, namely persistent inflammation and excessive extracellular matrix (ECM) deposition. In the present study, our aim was to evaluate the effectiveness of the herbal formulation Qishen Granule (QSG) against myocardial fibrosis.
METHODS: A model of HF with myocardial fibrosis was established by performing left anterior descending artery (LAD) ligation in mice. After three weeks of QSG treatment, cardiac function, fibrosis, and cardiac conduction were evaluated. We identified potential targets through network pharmacology and RNA sequencing analysis. The targeted effects of QSG were further validated using flow cytometry, Western blot, quantitative real-time PCR, and immunofluorescence techniques.
RESULTS: QSG can improve the heart function of HF mice, reduce myocardial inflammation and fibrosis, and effectively enhance cardiac conduction function. Its core mechanism lies in regulating the mechanosensitive ion channel Piezo1 and the calcium-dependent cysteine protease 2 (Calpain2) activation cascade, thereby blocking lysosome-associated membrane protein 1 (LAMP1) hydrolysis and cathepsin S (CTSS) release while reducing ECM deposition. In CCR2+ macrophages, QSG inhibits calcium influx by reducing Piezo1 expression, thereby suppressing myofibroblast activation. Knockdown of Piezo1 partially abrogates QSG's antifibrotic effects, confirming Piezo1 as an essential target for QSG's protective actions.
CONCLUSIONS: QSG reduces ECM deposition by targeting and inhibiting the Piezo1/Calpain2/LAMP1/CTSS signal axis in CCR2+ macrophages, thus improving myocardial fibrosis. This study provides a novel therapeutic strategy for HF-associated myocardial fibrosis by leveraging mechanosensitive signaling pathways.
METHODS: A model of HF with myocardial fibrosis was established by performing left anterior descending artery (LAD) ligation in mice. After three weeks of QSG treatment, cardiac function, fibrosis, and cardiac conduction were evaluated. We identified potential targets through network pharmacology and RNA sequencing analysis. The targeted effects of QSG were further validated using flow cytometry, Western blot, quantitative real-time PCR, and immunofluorescence techniques.
RESULTS: QSG can improve the heart function of HF mice, reduce myocardial inflammation and fibrosis, and effectively enhance cardiac conduction function. Its core mechanism lies in regulating the mechanosensitive ion channel Piezo1 and the calcium-dependent cysteine protease 2 (Calpain2) activation cascade, thereby blocking lysosome-associated membrane protein 1 (LAMP1) hydrolysis and cathepsin S (CTSS) release while reducing ECM deposition. In CCR2+ macrophages, QSG inhibits calcium influx by reducing Piezo1 expression, thereby suppressing myofibroblast activation. Knockdown of Piezo1 partially abrogates QSG's antifibrotic effects, confirming Piezo1 as an essential target for QSG's protective actions.
CONCLUSIONS: QSG reduces ECM deposition by targeting and inhibiting the Piezo1/Calpain2/LAMP1/CTSS signal axis in CCR2+ macrophages, thus improving myocardial fibrosis. This study provides a novel therapeutic strategy for HF-associated myocardial fibrosis by leveraging mechanosensitive signaling pathways.