The homeobox (HOX) family has shown potential in adipose development and function, yet the specific HOX proteins fueling adipose thermogenesis remain elusive. In this study, we uncovered the novel function of HOXC4 in stimulating adipose thermogenesis. Our bioinformatic analysis indicated an enrichment of Hoxc4 co-expressed genes in metabolic pathways and linked HOXC4 polymorphisms to metabolic parameters, suggesting its involvement in metabolic regulation. In mouse brown adipose tissue, HOXC4 expression negatively correlated with body weight and positively correlated with Ucp1 expression. Through gain- and loss-of-function experiments in mice, we established that HOXC4 is both sufficient and necessary for adipose thermogenesis, leading to enhanced cold tolerance and protection against diet-induced obesity and insulin resistance. Human and mouse primary adipocyte models further confirmed that the thermogenic activation function of HOXC4 is cell-autonomous. Mechanistically, HOXC4 collaborates with cofactor NCOA1 via its hexapeptide motif to form a transcriptional complex at the Ucp1 promoter, thereby promoting Ucp1 transcription and adipose thermogenesis. These findings delineate a novel mechanism by which HOXC4 drives thermogenic transcription and adipose energy metabolism, offering potential therapeutic targets for obesity-related metabolic disorders.© 2025 by the American Diabetes Association.