Combination of THU/ALK-5i exhibits profound anti-MASH activity through suppression of lipogenesis and fibrogenesis.

Metabolic dysfunction associated steatohepatitis (MASH), a progressive liver disease marked by steatosis, inflammation, and hepatocyte damage, is characterized by fibrosis, largely mediated by transforming growth factor-β (TGF-β). This study evaluated, as proof-of-concept, the therapeutic potential of tetrahydrocurcumin (THU), a curcumin derivative, in combination with EW-7197, an ALK-5 inhibitor, against MASH progression on in vitro and in vivo models. In vitro, TGF-β-treated hepatocytes (AML-12) and stellate cells (LX-2) were exposed to THU (1 µM), EW-7197 (0.5 µM), or their combination. EW-7197 mitigated TGF-β-induced hepatocyte morphological changes, while THU, alone or combined with EW-7197, reduced pathological lipid accumulation and counteracted EW-7197's adverse effects. In vivo, male C57BL/6J mice fed a methionine-choline deficient (MCD) diet for six weeks received oral EW-7197 (20 mg/kg) and THU (100 mg/kg). Co-administration effectively reduced liver fibrosis, improved MAFLD, and attenuated liver injury in MASH mice model. These findings suggest that the combination of THU and EW-7197 represents a promising therapeutic strategy for MAFLD/MASH by attenuating both liver fibrosis, and steatohepatitis more effectively than either monotherapy. While these findings highlight a synergistic anti-MASH effect of THU and EW-7197, the study is positioned as proof-of-concept. Further validation in metabolically relevant models (e.g., HFD/HFHC) and pharmacokinetic analyses are warranted before clinical translation can be considered.