Breaking the Heat Tolerance Response The Crucial Role of MFAP4 in Combating Heat Induced Cardiac Injury

1. MFAP4 deficiency exacerbates heatstroke (HS) induced injury. MFAP4-knockout (MFAP4 KO) mice exhibited significantly impaired thermotolerance, as indicated by an accelerated elevation of core temperature to 42.7, a prolonged recovery time to 36.5, and decreased survival rates. Furthermore, MFAP4 deficiency exacerbated cardiac dysfunction (reduced EF/FS) and potentiated myocardial pathological damage and fibrosis. 2. MFAP4 likely exerts its protective effect by stabilizing extracellular matrix (ECM) anchoring, thereby inhibiting sarcomere filament sliding and mitigating protection, potentially via the HSF1HSP70 axis 3. MFAP4 orchestrates transcriptional reprogramming in response to HS. MFAP4 deficiency drastically reduced the number of HS-responsive genes by 79% and reversed the expression direction of 98 genes, demonstrating its role in remodeling gene networks through epigenetic regulation. MFAP4 likely mediates its control over immune-cardio-thermoregulatory homeostasis by activating pathways such as Thermogenesis, cytosolic DNA-sensing, and vascular smooth muscle contraction, potentially via modulation of gene networks involving Zbp1, Cxcl10, and Fgf6.