Micranthin B alleviates metabolic dysfunction-associated steatohepatitis via targeting G3BP1 to improve stress granule-mediated endoplasmic reticulum stress

Ras-GTPase activating protein SH3 domain-binding protein 1 (G3BP1), a core component of stress granules (SGs), is highly expressed in several liver diseases, particularly in metabolic disorders where SG assembly has been observed. Targeting this process may offer a promising therapeutic strategy. A high-content drug screening based on G3BP1 expression identified Micranthin B (MB), a diterpenoid from Isodon lophanthoides (Buch.-Ham. ex D. Don) Hara, which alleviates metabolic dysfunction-associated steatohepatitis (MASH) by targeting G3BP1 to inhibit SG formation. MB administration significantly alleviated MASH progression in both high-fat, high-cholesterol (HFHC) diet-induced mouse models and palmitic acid (PA) -stimulated hepatocytes. Mechanistically, MB inhibits histone deacetylase 6 (HDAC6)-mediated deacetylation of G3BP1 to suppress SG formation, thereby preventing SG-mediated recruitment of N-glycosylation-associated proteins SEC61 translocon subunit beta (SEC61B) and calnexin (CANX), reducing the aggregation of misfolded or unfolded proteins and alleviating endoplasmic reticulum (ER) stress. These results suggest that MB has therapeutic potential in the treatment of MASH.