MANF is a neurotrophic factor that selectively promotes survival of dopaminergic neurons in the ventral midbrain and modulates GABAergic transmission to substantia nigra neurons. Beyond the nervous system, MANF functions as a broad cytoprotective protein that inhibits endoplasmic reticulum (ER) stress-induced cell death by stabilizing the ER chaperone HSPA5/BiP and repressing the unfolded protein response pathway. Under ER stress and hypoxia, MANF is secreted and binds sulfatide on target cell membranes, enabling cellular uptake required for its protective effects. MANF regulates immune responses in tissue injury contexts: it promotes repair-associated myeloid responses in skeletal muscle and limits excessive inflammation and NF-κB signaling in myocardial injury. MANF also supports embryonic lung development and postnatal skeletal development. Clinically, dysregulation of MANF has been implicated in multiple disease contexts. In breast cancer, MANF-mediated mitophagy facilitates cell survival under glucose starvation and promotes fatty acid oxidation; high MANF expression predicts poor outcomes 1. MANF deficiency exacerbates hepatic fibrosis by impairing macrophage regulation of the S100A8/A9-TLR4-NF-κB pathway 2. In immune checkpoint inhibitor-treated patients, MANF downregulation in cardiac tissue contributes to myocarditis, particularly in females; recombinant MANF protein attenuates this cardiotoxicity 3. Conversely, systemic MANF administration alleviates dietary obesity and metabolic disorders in mice 4, and emerging evidence suggests MANF as a promising target for metabolic diseases and potentially as a biomarker in intrahepatic cholangiocarcinoma 5.