BACKGROUND: Scar formation is a common end-point of the wound healing process, but its mechanisms, particularly in relation to abnormal scars such as hypertrophic scars and keloids, remain not fully understood. This study unveils a novel mechanistic insight into scar formation by examining the differential expression of Homeobox (HOX) genes in response to mechanical forces in fibroblasts derived from normal skin, hypertrophic scars, and keloids. METHODS: We isolated fibroblasts from different scar types and conducted RNA sequencing (RNA-Seq) to identify differential gene expression patterns among the fibroblasts. Computational modeling provided insight into tension alterations following injury, and these findings were complemented by in vitro experiments where fibroblasts were subjected to exogenous tensile stress to investigate the link between mechanical tension and cellular behavior. RESULTS: Our study revealed differential HOX gene expression among fibroblasts derived from normal skin, hypertrophic scars, and keloids. Computational simulations predicted injury-induced tension reduction in the skin, and in vitro experiments revealed a negative correlation between tension and fibroblast proliferation. Importantly, we discovered that applying mechanical tension to fibroblasts can modulate HOX gene expression, suggesting a pivotal role of mechanical cues in scar formation and wound healing. CONCLUSION: This study proposes a model wherein successful wound healing and scar formation are critically dependent on maintaining tensional homeostasis in the skin, mediated by tension-sensitive HOX genes. Our findings highlight the potential of targeting mechanotransduction pathways and tension-sensitive HOX gene expression as therapeutic strategies for abnormal scar prevention and treatment, offering a new perspective on the complex process of scar formation.