Genetic and Molecular Basis of Heat Stress Resilience in Pigs: Mechanisms, Genomic Regions, and Breeding Perspectives

Background/Objectives: Heat stress is one of the most economically and physiologically important constraints on pig (Sus scrofa domesticus) production, affecting welfare, reducing feed intake, growth, and reproductive efficiency, while increasing morbidity and mortality; because pigs lack functional eccrine sweat glands and have a limited capacity for evaporative heat dissipation, their ability to cope with high ambient temperature depends heavily on behavioral, physiological, and cellular stress-response mechanisms, which vary among individuals and genetic backgrounds. This review synthesizes current knowledge of the genetic and molecular pathways underlying the pig heat-stress response, spanning the HSF1–heat shock protein axis and epigenetic regulation, as well as genomic regions, candidate genes, nutrigenomic modulation, and reproductive consequences in boars and sows. Methods: A narrative literature review, informed by key principles of the PRISMA 2020 statement, synthesized 58 peer-reviewed transcriptomic, genomic, epigenomic, proteomic, and physiological studies published mainly between 1998 and 2026. Results: Heat exposure activates HSF1-driven heat shock protein transcription, oxidative stress, gut tight-junction disruption, hypothalamic–pituitary proteomic remodeling, and sex-dimorphic apoptotic/inflammatory transcriptional programs that also compromise boar semen quality. GWAS and QTL studies have mapped genomic regions and candidate genes for thermoregulatory, reproductive, and growth traits. At the same time, breed comparisons suggest, but do not prove on their own, a genetic contribution to the smaller physiological responses observed in some tropical and Mediterranean-adapted breeds. Heritability estimates for individual heat-stress-related traits, rather than for heat tolerance as a composite phenotype, range from low (0.02–0.20) for reproductive traits, to moderate (0.35–0.39) for thermoregulatory traits in lactating sows, to moderate-to-high (0.49–0.83) for physiological responses to acute heat challenge in gilts; circulating cortisol (h2 ≈ 0.68) is a heritable biomarker of the stress response rather than a measure of heat tolerance itself. Conclusions: Several traits associated with the response to heat stress in pigs are heritable and polygenic, supporting the potential of genomic selection, reaction-norm modeling, and marker-assisted introgression, although functional validation of candidate genes and larger multi-population studies, together with an explicit definition of heat tolerance as a composite selection objective, remain priorities.