Frontiers in pharmacology · 2026
Senkyunolide I and Danshensu in combination ameliorate post-MI myocardial fibrosis by regulating TGF-β1/PAI-1 in mice and heart organoids.
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Fan Siwen, Shi Mengxu, Zhao Yuhan, Nie Wenan, Yao Yixin, Han Linhong, He Shuang, Xiao Guangxu, Zhu Yan
Аннотация
BACKGROUND: Myocardial fibrosis following myocardial infarction (MI) is a critical determinant of long-term clinical outcomes in heart disease. However, this central pathological process in the progression from MI to heart failure is not fully understood, posing challenges for targeted therapeutic options.
PURPOSE: This study aimed to identify new targets critical to myocardial fibrosis after MI and to evaluate the potential of Guanxinning injection (GXNI, a combination of Danshen and Chuanxiong) to suppress post-MI myocardial fibrosis.
METHODS: A MI mouse model was established by permanent ligation of the left anterior descending artery. Therapeutic effects were assessed by echocardiography and histopathology. HPLC chromatography, Network pharmacology, molecular docking, two-dimensional primary cell cultures, and iPS-induced cardiac organoid models were employed to identify active components and investigate underlying mechanisms.
RESULTS: GXNI reduced myocardial fibrosis and injury, improving cardiac function. Network pharmacology and molecular docking identified Senkyunolide I (SENI) and Danshensu (DSS) as the key active components acting via the TGF-β1/PAI-1 pathway. Thermal shift assay demonstrated direct binding of SENI and DSS to PAI-1. In vitro and cryoinjury cardiac organoid models confirmed that GXNI and the SENI-DSS combination inhibited fibroblast activation and TGF-β1/PAI-1 expression, reducing fibrosis.
CONCLUSION: We demonstrate for the first time that the TGF-β1/PAI-1 signaling pathway plays a critical role in post-MI myocardial fibrosis, and GXNI attenuates MI via this pathway. Secondly, the active components of GXNI, SENI and DSS, act combinatorially to enhance the anti-fibrotic therapeutic efficacy. Furthermore, cryoinjury cardiac organoids serve as a powerful platform for investigating the mechanisms underlying myocardial infarction.
PURPOSE: This study aimed to identify new targets critical to myocardial fibrosis after MI and to evaluate the potential of Guanxinning injection (GXNI, a combination of Danshen and Chuanxiong) to suppress post-MI myocardial fibrosis.
METHODS: A MI mouse model was established by permanent ligation of the left anterior descending artery. Therapeutic effects were assessed by echocardiography and histopathology. HPLC chromatography, Network pharmacology, molecular docking, two-dimensional primary cell cultures, and iPS-induced cardiac organoid models were employed to identify active components and investigate underlying mechanisms.
RESULTS: GXNI reduced myocardial fibrosis and injury, improving cardiac function. Network pharmacology and molecular docking identified Senkyunolide I (SENI) and Danshensu (DSS) as the key active components acting via the TGF-β1/PAI-1 pathway. Thermal shift assay demonstrated direct binding of SENI and DSS to PAI-1. In vitro and cryoinjury cardiac organoid models confirmed that GXNI and the SENI-DSS combination inhibited fibroblast activation and TGF-β1/PAI-1 expression, reducing fibrosis.
CONCLUSION: We demonstrate for the first time that the TGF-β1/PAI-1 signaling pathway plays a critical role in post-MI myocardial fibrosis, and GXNI attenuates MI via this pathway. Secondly, the active components of GXNI, SENI and DSS, act combinatorially to enhance the anti-fibrotic therapeutic efficacy. Furthermore, cryoinjury cardiac organoids serve as a powerful platform for investigating the mechanisms underlying myocardial infarction.