In 2024, resmetirom (MGL-3196) became the first FDA-approved drug for MASH, demonstrating significant efficacy in resolving MASH without worsening fibrosis in 27% of patients, compared to 10% in the placebo group. This selective THR-β agonist targets the thyroid hormone receptor in the liver, improving β-oxidation, autophagy, and providing anti-inflammatory and anti-fibrotic effects. A new compound, HSK31679, developed from resmetirom’s structure, showed enhanced efficacy in treating MASH. This improvement is likely due to its interaction with gut microbiota, particularly Bacteroides thetaiotaomicron, which produces anti-inflammatory sphingolipids.

Studies revealed that HSK31679 treatment led to shifts in gut microbiota, including increased B. thetaiotaomicron, which influenced sphingolipid metabolism and contributed to its effects. The drug’s efficacy appears to depend on the presence of specific gut microbes. This suggests that patients with low levels of B. thetaiotaomicron may have a reduced response to THR-β agonist therapy. Researchers suggest that future research should focus on microbiota-modulating treatments to improve efficacy in non-responders to MASH-targeting therapies like HSK31679.

Reference: Meijnikman AS, Bruinstroop E. Non-responder on thyroid hormone receptor-β agonist? Bacteroides thetaiotaomicron to the rescue! J Hepatol. 2025 Feb;82(2):165-167. doi: 10.1016/j.jhep.2024.11.009. Epub 2024 Nov 14. PMID: 39550038.