Multi-omics dissection of heat stress reveals CIITA as a central regulator of metabolic thermotolerance in cattle (Bos taurus).

Climate-driven heat stress disrupts metabolic homeostasis in livestock, yet the molecular mechanisms underlying adaptive responses remain poorly understood. Here, we integrated newly generated plasma metabolomic data from 111 heat-stressed cows with previously published whole-genome sequencing datasets from the same animals, identifying 30 metabolic markers and 27 copy number variations (CNVs) associated with 25 candidate genes involved in the regulation of these metabolites. Notably, a CNV hotspot encompassing CIITA emerged as a key pleiotropic locus strongly associated with acylcarnitine levels, body weight, and rectal temperature. Heat exposure suppressed CIITA expression in skeletal muscle, correlating with impaired myogenic development. We demonstrate that CIITA overexpression in vitro induces coordinated remodeling of cell cycle-related gene expression and partially alleviates heat-induced inhibition of myoblast proliferation. Moreover, CIITA overexpression markedly suppresses long-chain fatty acid β-oxidation and mitochondrial electron transport activity, accompanied by reduced adenosine triphosphate production, suggesting that CIITA may limit metabolic heat generation by constraining mitochondrial metabolic flux. Overall, these findings position CIITA as a central integrative regulator linking immune function, energy metabolism, and cell proliferation during bovine adaptation to heat stress, and highlight a potential genetic target for improving thermotolerance in livestock.