Manf, short for Mesencephalic astrocyte-derived neurotrophic factor, is an endoplasmic reticulum-resident and secretory protein. It has cytoprotective effects in neurons and pancreatic β cells [2]. MANF is involved in regulating the unfolded protein response (UPR) through interaction with its ER-located receptor IRE1α, which is crucial for neuronal survival [2]. It also plays important roles in multiple biological processes and diseases, such as metabolic diseases, neurodegenerative disorders, and hepatic fibrosis [1,3,4].

In metabolic diseases, mouse models have shown that Manf down-regulation impairs glucose homeostasis, promotes lipid accumulation in the liver, reduces energy expenditure, and induces inflammation, while overexpression prevents or mitigates these metabolic disturbances. Systemic Manf administration alleviates dietary obesity and related metabolic disorders in obese mice, indicating its potential as a therapeutic target for chronic metabolic diseases [1].

In hepatic fibrosis, Manf deficiency in hepatic mono-macrophages exacerbates hepatic fibrosis, while myeloid-specific Manf knockout increases the population of hepatic Ly6Chigh macrophages and promotes HSCs activation. Recombinant human Manf administration significantly alleviates CCl4-induced hepatic fibrosis [4].

In conclusion, Manf has essential functions in maintaining cellular homeostasis, especially in relation to ER stress and UPR. Gene knockout mouse models have revealed its roles in metabolic diseases and hepatic fibrosis, highlighting its potential as a therapeutic target in these disease areas.