The role of mesencephalic astrocyte-derived neurotrophic factor in digestive diseases.

[BACKGROUND] Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an evolutionarily conserved endoplasmic reticulum (ER)-resident and secreted protein highly expressed in the digestive system. Emerging evidence has highlighted its pivotal roles in liver diseases, as well as in other digestive diseases including intestinal and pancreatic disorders. This review summarizes the expression, molecular mechanisms, and pathological roles of MANF in digestive diseases and evaluates its translational potential as a therapeutic target and biomarker.

[DISCUSSION] MANF exerts effects primarily through ER stress regulation, antioxidative responses, and regulation of inflammatory signaling cascades. In liver diseases, MANF plays a context-dependent dual roles. It protects against alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), hepatocellular carcinoma (HCC), drug-induced liver injury (DILI), and ischemia/reperfusion injury, yet promotes immune tolerance in chronic hepatitis B virus (HBV) infection and acts as an oncogenic driver in intrahepatic cholangiocarcinoma (ICC). In pancreatic disorders, MANF protects β-cells from ER stress-induced apoptosis in diabetes and mitigates acute pancreatitis. In intestinal diseases, it ameliorates inflammatory bowel disease (IBD) and necrotizing enterocolitis (NEC). The function of MANF are determined by cellular context, disease stage, and specific microenvironmental signals.

[CONCLUSION] MANF emerges as a key regulator of digestive tract homeostasis. Targeting MANF may represent a potential therapeutic strategy for preventing and treating digestive diseases. Its dynamic expression patterns also suggest possible biomarker utility. Further studies are needed to optimize targeted interventions and validate its clinical translation.