Role of Homeobox (HOX) Genes in Adult Cardiovascular Disease: From Developmental Regulators to Therapeutic Targets.

Homeobox (HOX) genes, once primarily viewed as regulators of embryonic development, are now acknowledged as important factors in adult cardiovascular pathophysiology. This narrative review consolidates existing knowledge from developmental biology, molecular cardiology, and translational medicine to clarify the roles of HOX genes in cardiovascular disease, emphasizing molecular mechanisms and therapeutic ramifications. HOX genes operate as context-dependent molecular switches, exhibiting unique roles specific to various diseases. HOXA5 safeguards against atherosclerosis via peroxisome proliferator-activated receptor gamma (PPARγ), whereas HOXB9 exacerbates inflammation through bone morphogenetic protein 4-tumor necrosis factor (BMP4-TNF). HOXA4 demonstrates dual functionality, safeguarding against vascular remodeling while facilitating cardiac fibrosis. Functional specificity is attained via trimeric complexes comprising pre-B-cell leukemia homeobox (PBX) and myeloid ecotropic viral integration site (MEIS) proteins, with epigenetic modifications facilitating dynamic regulation. Therapeutic strategies, such as HOX-PBX inhibition, epigenetic modulation, and gene therapy, exhibit encouraging preclinical outcomes. HOX genes serve as principal regulators of the cardiovascular system, and their dysfunction markedly influences disease development, thereby establishing HOX-targeted therapies as innovative precision medicine strategies necessitating expedited clinical translation.