KR-36996, an orally active urotensin II receptor antagonist, attenuates hepatic inflammation and fibrosis in methionine- and choline-deficient diet-induced fibrosing steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of metabolic dysfunction-associated steatotic liver disease, is characterized by hepatocellular injury, chronic inflammation, and fibrosis, yet effective antifibrotic therapies remain limited. The urotensin II (UII)/urotensin II receptor (UTR) system has been implicated in injury and tissue remodeling in several chronic liver conditions, but its role in MASH remains unclear. We examined KR-36996, an orally active UTR antagonist, in a methionine- and choline-deficient (MCD) diet-induced mouse model of fibrosing steatohepatitis. Male C57BL/6 mice were fed the MCD diet for 4 weeks and treated orally with KR-36996 at 30 mg/kg/day. Liver injury, steatosis, inflammation, fibrosis, hepatic UII/UTR expression, and MAPK signaling were assessed by serum biochemistry, histology, immunohistochemistry, RT-qPCR, and Western blotting. KR-36996 reduced serum alanine aminotransferase and aspartate aminotransferase levels and attenuated hepatic inflammation, with fewer inflammatory foci, reduced F4/80-positive macrophage accumulation, and lower Il1b, Ccl2, and Tnf expression. It also decreased collagen deposition, α-smooth muscle actin immunoreactivity, and the fibrogenic markers Col1a1 and Timp1. MCD feeding increased hepatic UII and UTR protein levels and enhanced JNK phosphorylation; KR-36996 reduced JNK phosphorylation, whereas ERK and p38 phosphorylation remained unchanged. These findings indicate that UTR antagonism primarily attenuates inflammatory and fibrogenic responses, whereas evidence for an antisteatotic effect was limited in this model, and support further evaluation of the UII/UTR axis as a potential therapeutic target for the inflammatory and fibrotic components of steatohepatitis.