MANF (mesencephalic astrocyte-derived neurotrophic factor) is a multifunctional protein that serves as both an endoplasmic reticulum (ER)-resident chaperone and a secreted neurotrophic factor. MANF selectively promotes survival of dopaminergic neurons and modulates GABAergic transmission in the substantia nigra 1. The protein functions as a critical regulator of ER stress responses by stabilizing HSPA5/BiP in its substrate-bound state and repressing the unfolded protein response pathway under normal conditions 2. Under stress conditions, MANF is upregulated and secreted, where it binds to sulfatide receptors on target cells to alleviate ER stress and cell toxicity 2. MANF exhibits significant therapeutic potential in metabolic diseases, with circulating levels dynamically regulated in diabetes, obesity, and cardiovascular diseases 3. In cancer, MANF facilitates cell survival under glucose starvation by regulating PRKN-mediated mitophagy and promoting fatty acid oxidation 4. The protein also modulates immune responses by competitively binding S100A8 to inhibit TLR4-NF-κB signaling and regulate macrophage phenotypes 5. Clinically, MANF shows promise as a biomarker and therapeutic target for various diseases including immune checkpoint inhibitor myocarditis, hepatic fibrosis, and intrahepatic cholangiocarcinoma 657.