Atractylodes macrocephala Koidz. Polysaccharides Alleviate Liver Fibrosis in Association With Suppression of cGAS-STING Signaling and Mitochondrial Apoptosis.
ETHNOPHARMACOLOGICAL RELEVANCE Atractylodes macrocephala Koidz. is a premier tonic herb in East Asian medicine, traditionally used to strengthen the spleen, resolve dampness, and treat digestive ailments. While its clinical efficacy in metabolic and immune disorders is well-recognized, the specific therapeutic potential and molecular mechanisms of Atractylodes macrocephala Koidz. polysaccharides (AMPs) against liver fibrosis remain to be fully elucidated. AIM OF THE STUDY This study aimed to evaluate the hepatoprotective and anti-fibrotic effects of AMPs and to examine the associated mechanisms, with emphasis on mitochondrial injury-related indicators and cGAS-STING/NLRP3 inflammatory activation. METHODS Liver fibrosis was induced in C57BL/6 mice using three etiologically distinct and complementary models: a methionine-choline-deficient (MCD) diet, carbon tetrachloride (CCl4) injections, and bile duct ligation (BDL). AMPs (100 and 200 mg/kg) were administered daily by oral gavage. Liver injury, fibrosis severity, and macrophage infiltration were assessed using histopathology, immunohistochemistry, and biochemical analyses. Transcriptomic profiling was used to identify differentially expressed genes, and the association of AMPs with mitochondrial DNA (mtDNA)-related danger signaling and cGAS-STING inflammatory activation was examined by qPCR, immunofluorescence, and Western blotting. RESULTS AMPs consistently attenuated liver injury and fibrosis across all three models, accompanied by reduced STING activation predominantly localized to F4/80+ macrophages and decreased CD68+ macrophage infiltration. These improvements were associated with suppression of the cGAS-STING-NLRP3 inflammatory cascade and downregulation of macrophage-related transcriptional programs, concordant with improved biochemical indices and fibrosis severity. CONCLUSION Collectively, these findings suggest that AMPs exert antifibrotic activity in experimental liver fibrosis. This activity was associated with reduced cGAS-STING/NLRP3 inflammatory activation and modulation of mitochondria-associated apoptotic signaling, supporting further focused mechanistic evaluation of AMPs in fibrotic liver disease.