Blocking Succinate–GPR91 Signaling in MASH: Hepatology | April 2026

Introduction:

Liver fibrosis is the key determinant of long-term outcomes in metabolic dysfunction-associated steatohepatitis (MASH). Activated hepatic stellate cells (HSCs) drive fibrogenesis, but effective antifibrotic therapies remain unavailable. This study investigated whether blocking the succinate–GPR91 signaling pathway in HSCs could halt fibrosis progression.

Why was this study needed?

• Liver fibrosis is the strongest predictor of liver-related mortality in MASH.
• Hepatic stellate cells are the principal drivers of fibrosis.
• Succinate accumulates during metabolic liver injury and activates HSCs through the GPR91 receptor.
• The therapeutic potential of targeting GPR91 had not been confirmed in vivo.
• Novel molecular targets are urgently needed to prevent fibrosis progression.

Results:

• Blocking GPR91 specifically in hepatic stellate cells markedly reduced liver fibrosis, collagen deposition, and fibrogenic activity in experimental MASH.
• Succinate promoted hepatic stellate cell activation and survival, whereas GPR91 inhibition suppressed profibrotic signaling and enhanced HSC apoptosis.
• These findings identify the succinate–GPR91 pathway as a key driver of MASH fibrosis and a promising therapeutic target for future antifibrotic therapies.

Clinical Impact:

This study identifies a novel metabolic signaling pathway linking succinate accumulation to hepatic stellate cell activation and fibrosis. Targeting GPR91 could represent a new class of antifibrotic therapy capable of slowing or preventing fibrosis progression in patients with MASH.

Bottom Line:

The succinate–GPR91 signaling pathway is a major driver of liver fibrosis in MASH. Blocking GPR91 effectively suppresses hepatic stellate cell activation and fibrosis, making it a promising target for next-generation antifibrotic therapies.