Mechanistic role of mesencephalic astrocyte-derived neurotrophic factor in myocardial ischemia/reperfusion injury

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a protein crucial for cellular stress response and survival, particularly in the nervous and cardiovascular systems. Unlike traditional neurotrophic factors, MANF primarily regulates endoplasmic reticulum (ER) stress and protects cells by reducing ER stress-induced apoptosis. MANF operates both inside and outside cells, influencing key pathways like JAK/STAT and NF-κB to enhance cell survival during stress. Beyond its neuroprotective role, MANF is also vital in cardiovascular protection, mitigating damage by reducing inflammation and maintaining cellular function. Elevated MANF levels have been observed in patients experiencing myocardial infarction and murine models of ischemia–reperfusion (I/R) injury, highlighting its importance in these conditions. Overexpression of MANF in cardiomyocytes reduces ER-stress-induced cell death, while its depletion worsens this effect. Treatment with recombinant MANF (rMANF) has been shown to improve cardiac function in mice with I/R injury by decreasing infarct size and inflammation. Research also indicates that alterations in the α1-helix region of MANF can impact its structure, expression, secretion, and overall function. Given its protective effects and involvement in critical signaling pathways, MANF is being explored as a potential therapeutic target for ER stress-related diseases, including neurodegenerative disorders and cardiovascular conditions like myocardial I/R injury.