Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Piezo1 as a novel therapeutic target of salvianolic acid B for metabolic dysfunction-associated steatotic liver disease.
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Zhang Yuxue, Liu Chang, He Weiyi, Li Wenhui, Duan Wentao, Wu Chaofeng, Jia Hui, Lan Jieying, Tong Zeyu, Du Qiaohui, Lin Haiyan, Gao Zhuowei, Zhao Wenxia, Luo Piao, Gao Lei
Аннотация
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of liver diseases worldwide and imposes an increasingly heavy burden on society. After years of research, salvianolic acid B (Sal B), the main component of traditional Chinese medicine Salvia miltiorrhiza, exhibits significant efficacy in alleviating fatty liver; however, its precise mechanism of action against MASLD remains unclear.
PURPOSE: This study aimed to investigate the underlying pharmacological mechanism of Sal B in treating MASLD, using both in vivo and in vitro models.
STUDY DESIGN: A systematic pharmacology approach combining multi-species phenotypic screening with proteomics and molecular target verification was employed to elucidate the mechanism of Sal B against MASLD.
METHODS: MASLD models were established in thioacetamide‑treated zebrafish, MCD diet‑fed mice, and oleate/palmitate‑exposed AML12 hepatocytes. The therapeutic effects of Sal B were assessed by histology, proteomics, Seahorse metabolic analysis, calcium imaging, flow cytometry, and molecular binding assays such As spr, CETSA, and competitive labeling. The involvement of Piezo1 and the C215 residue was examined by siRNA‑mediated knockdown, NEM competition, and expression of wild‑type versus C215S mutant protein.
RESULTS: Sal B treatment was associated with reduced hepatic lipid accumulation, inflammation, oxidative stress, and energy metabolism disturbances in all three models. Proteomic analysis suggested modulation of a PPAR‑centered metabolic network. Sal B appeared to interact with the Piezo1 extracellular domain, and the C215S mutation markedly decreased this interaction. In Piezo1‑overexpressing HEK293T cells, Sal B attenuated YODA1‑induced Ca²⁺ influx; this effect was not observed following NEM pretreatment or Piezo1 knockdown. Sal B also reduced YODA1‑elicited mitochondrial Ca²⁺ overload and ROS production in AML12 cells, effects that were less evident when Piezo1 was knocked down. Moreover, Piezo1 knockdown alone produced changes in PPAR‑related genes similar to those induced by Sal B, and adding Sal B to knockdown cells did not lead to further alterations.
CONCLUSION: The available evidence suggests that Sal B can inhibit Piezo1 channel activity, possibly through interaction with cysteine 215 in its extracellular domain, and that this may contribute to alleviation of mitochondrial Ca²⁺ overload, oxidative stress, and metabolic dysregulation in MASLD models. Importantly, the identification of C215 as the binding site is based on computational prediction and SPR assays using the truncated extracellular domain; direct functional confirmation with full‑length C215S mutant protein remains to be performed. These findings point to C215 as a candidate binding residue for Sal B and support further investigation of Piezo1‑targeted strategies for MASLD.
PURPOSE: This study aimed to investigate the underlying pharmacological mechanism of Sal B in treating MASLD, using both in vivo and in vitro models.
STUDY DESIGN: A systematic pharmacology approach combining multi-species phenotypic screening with proteomics and molecular target verification was employed to elucidate the mechanism of Sal B against MASLD.
METHODS: MASLD models were established in thioacetamide‑treated zebrafish, MCD diet‑fed mice, and oleate/palmitate‑exposed AML12 hepatocytes. The therapeutic effects of Sal B were assessed by histology, proteomics, Seahorse metabolic analysis, calcium imaging, flow cytometry, and molecular binding assays such As spr, CETSA, and competitive labeling. The involvement of Piezo1 and the C215 residue was examined by siRNA‑mediated knockdown, NEM competition, and expression of wild‑type versus C215S mutant protein.
RESULTS: Sal B treatment was associated with reduced hepatic lipid accumulation, inflammation, oxidative stress, and energy metabolism disturbances in all three models. Proteomic analysis suggested modulation of a PPAR‑centered metabolic network. Sal B appeared to interact with the Piezo1 extracellular domain, and the C215S mutation markedly decreased this interaction. In Piezo1‑overexpressing HEK293T cells, Sal B attenuated YODA1‑induced Ca²⁺ influx; this effect was not observed following NEM pretreatment or Piezo1 knockdown. Sal B also reduced YODA1‑elicited mitochondrial Ca²⁺ overload and ROS production in AML12 cells, effects that were less evident when Piezo1 was knocked down. Moreover, Piezo1 knockdown alone produced changes in PPAR‑related genes similar to those induced by Sal B, and adding Sal B to knockdown cells did not lead to further alterations.
CONCLUSION: The available evidence suggests that Sal B can inhibit Piezo1 channel activity, possibly through interaction with cysteine 215 in its extracellular domain, and that this may contribute to alleviation of mitochondrial Ca²⁺ overload, oxidative stress, and metabolic dysregulation in MASLD models. Importantly, the identification of C215 as the binding site is based on computational prediction and SPR assays using the truncated extracellular domain; direct functional confirmation with full‑length C215S mutant protein remains to be performed. These findings point to C215 as a candidate binding residue for Sal B and support further investigation of Piezo1‑targeted strategies for MASLD.