How Substance P Drives Liver Scarring Through Opposing Effects on Cell Aging

Researchers used multiple mouse models: wild-type and NK-1R knockout mice that underwent bile duct ligation (BDL) or sham surgery, and Mdr2 knockout mice treated with either the NK-1R antagonist L-733,060 or saline. Wild-type mice were also treated with Substance P or saline. Liver fibrosis was measured by sirius red staining, fibrosis gene/protein expression, and TGF-β1 levels. Cellular senescence was assessed in hepatic stellate cells and cholangiocytes. Human liver tissue from primary sclerosing cholangitis patients was also analyzed.

Liver fibrosis is a major driver of chronic liver disease progression, and current treatments are limited. This study identifies the Substance P/NK-1R signaling pathway as a potential therapeutic target — and an NK-1R antagonist (L-733,060) already reduced fibrosis in two different mouse models. The fact that human liver tissue from primary sclerosing cholangitis patients showed the same elevated SP/NK-1R expression suggests this pathway is clinically relevant.

This study adds Substance P to the growing list of neuropeptides that influence organ fibrosis beyond their traditional roles in pain and inflammation. If NK-1R antagonists — some of which already exist as approved drugs for other conditions — prove effective against liver fibrosis in humans, it could open a repurposing pathway for treating chronic liver disease.

This is primarily an animal study using mouse models, so results may not fully translate to human liver disease. While human PSC tissue showed elevated SP/NK-1R expression, no therapeutic interventions were tested in human subjects. The NK-1R antagonist L-733,060 has not been evaluated in clinical trials for liver fibrosis.