Abstract: Ras-GTPase activating protein SH3 domain-binding protein 1 (G3BP1), a core component of stress granules (SGs), is highly expressed in several liver diseases. SG assembly has also been observed in metabolic disorders, suggesting that this process may be a promising therapeutic target. Using a high-content drug screening approach based on G3BP1 expression, we identified Micranthin B (MB), a diterpenoid from Isodon lophanthoides (Buch.-Ham. ex D. Don) Hara, as a compound that alleviates metabolic dysfunction-associated steatohepatitis (MASH) by targeting G3BP1 and inhibiting 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 inhibited histone deacetylase 6 (HDAC6)-mediated deacetylation of G3BP1, thereby suppressing SG formation. This prevented SG-mediated recruitment of the N-glycosylation-related proteins SEC61 translocon subunit beta (SEC61B) and calnexin (CANX), reduced the accumulation of misfolded or unfolded proteins, and alleviated endoplasmic reticulum (ER) stress. These findings suggest that MB has therapeutic potential in the treatment of MASH.