Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum-resident and secretory protein. It has cytoprotective effects in neurons and pancreatic β cells, regulates the unfolded protein response (UPR) through interacting with IRE1α, and plays crucial roles in multiple biological processes and disease conditions. MANF is composed of an N-terminal saposin-like lipid-binding domain and a C-terminal SAP domain [2]. It's involved in maintaining proteostasis and is a UPR responsive gene [6].

In mouse models, MANF downregulation impairs glucose homeostasis, promotes lipid accumulation in the liver, reduces energy expenditure, and induces inflammation. Conversely, overexpression prevents or mitigates some of these metabolic disturbances. For example, systemic MANF administration alleviates dietary obesity and related metabolic disorders in obese mice, suggesting its potential as a treatment for chronic metabolic diseases [1]. In the context of hepatic fibrosis, MANF deficiency in hepatic mono-macrophages exacerbates fibrosis, while recombinant MANF administration alleviates CCl4-induced hepatic fibrosis in mice [3]. In breast cancer cells, MANF-mediated mitophagy promotes cell survival under glucose-starvation conditions, and high MANF expression predicts poor outcomes in breast cancer patients [4]. In the heart, down-regulation of MANF is associated with immune checkpoint inhibitor (ICI)-induced myocarditis, and administration of recombinant MANF protein attenuates this effect [5]. In an autosomal dominant tubulointerstitial kidney disease mouse model, inducible tubular overexpression of MANF stimulates autophagy/mitophagy, clears mutant UMOD, and protects kidney function, while genetic ablation of MANF worsens autophagy suppression and kidney fibrosis [7].

In conclusion, MANF has diverse essential biological functions, including regulating metabolism, protecting against tissue fibrosis, influencing cancer cell survival, and maintaining heart and kidney functions. Mouse models, especially those with MANF knockout or overexpression, have been instrumental in revealing its role in these specific disease areas, highlighting its potential as a therapeutic target for metabolic, hepatic, cardiac, renal, and cancer-related diseases.