Salidroside alleviates metabolic dysfunction-associated steatohepatitis-induced fibrosis by regulating PI3K/AKT/mTOR pathway-mediated hepatocyte mitophagy.

BACKGROUND

Salidroside (SAL), the primary active compound extracted from Rhodiola rosea, has demonstrated potential efficacy against MASH-induced fibrosis; however, its precise pharmacological mechanisms and molecular targets remain incompletely elucidated.

PURPOSE: The aim of this study was to explore the protective effects of against MASH-induced liver fibrosis and its underlying pharmacological mechanisms.

METHODS

In this work, a MASH-induced fibrosis model was established using the high-fat diet (HFD) and choline-deficient, L-amino acid-defined (CDAHFD) diet-fed in vivo and palmitic acid/oleic acid-stimulated hepatocytes in vitro. By comprehensively conducting biochemical index measurements, pathological analysis, Western blot, PCR detection, RNA sequencing, 4D-DIA proteomic analyses, molecular docking, and validation experiments, the study revealed the critical association of PI3K/AKT/mTOR-mediated autophagy-associated mitochondrial quality control with the treatment of MASH-related liver fibrosis.

RESULTS

Sal treatment significantly ameliorates hepatic steatosis, inflammatory infiltration, and liver fibrosis induced by CDAHFD and HFD. Integrated RNA sequencing and 4D-DIA proteomics analysis revealed that the anti-fibrotic effect of Sal on MASH-induced liver fibrosis may be associated with regulation of the PI3K/AKT/mTOR signaling pathway, thereby enhancing autophagy-associated mitochondrial quality control in hepatocytes, preventing cytoplasmic accumulation of mitochondrial DNA (mtDNA), and ultimately blocking the activation of the cGAS-STING pathway and subsequent production of pro-inflammatory cytokines, including TNF-α and IL-1β. Further in vivo and in vitro andvalidation experiments demonstrated that the anti-fibrotic effects of Sal could be reversed by combined treatment with PI3K or mTOR agonists, specifically manifested as activation of the PI3K/AKT/mTOR signaling pathway, reduced hepatocyte mitochondrial autophagy, restoration of cGAS-STING pathway activity, and increased production of pro-inflammatory cytokines.

CONCLUSION

In summary, Our findings demonstrate that SAL mitigates MASH-induced liver fibrosis by targeting hepatocyte autophagy-associated mitochondrial quality control to suppress the mtDNA-dependent cGAS-STING inflammatory pathway, thereby revealing a novel therapeutic strategy.