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

Heat exposure increases cardiac workload and impairs thermoregulation, leading to cardiac injury and heatstroke (HS). The involvement of Microfibrillar‐associated protein 4 (MFAP4) in HS remains unclear. This study aims to investigate the role and mechanisms of MFAP4 in heat‐induced damage. Whole body MFAP4‐knockout (MFAP4‐KO) mice and MFAP4‐overexpressing cells were generated. Physiological and pathological responses were assessed in vivo/vitro experiments. An HS model exposed mice to (39.5 ± 0.5)°C/(55 ± 5)% humidity; and cell to 44°C with 5% CO₂ for 2 h. Transcriptomic analysis was performed to investigate the mechanisms underlying myocardial injury. MFAP4‐KO mice exhibited accelerated core temperature rise, recovery of core temperature to 36.5°C was delayed, and reduced survival during HS ( p < 0.05). HS induced left ventricular dilation (elevated LVIDd/LVIDs), systolic dysfunction (reduced EF/FS), myocardial injury (increased serum cTnT/cTnI), and fibrosis, all of which were exacerbated by MFAP4 deficiency. HS significantly elevated MFAP4 levels in serum and aorta, while MFAP4 deficiency mice hearts showed compensatory activation of the HSF1/HSP70 signaling pathway. MFAP4 overexpression increased cellular resistance to HS. Transcriptomic analysis revealed a 79% reduction in heat‐responsive genes, and reversed 98 genes, confirming MFAP4 as a central cardiac protective role regulator of HS. MFAP4 deficiency also influenced Zbp1, Ccl12 , and Cxcl10 expression through thermogenesis, and vascular smooth muscle contraction pathways. MFAP4 is a critical mediator of cardiovascular protection during acute HS. Its deficiency leads to thermoregulatory failure, and disrupts myocardial proteostasis by impairing the HSF1/HSP70 signaling axis, thereby exacerbating cardiac injury. MFAP4 likely increases myocardial resilience by regulating a ZBP1/CXCL10‐centered network, thereby exerting a cardioprotective effect.