Fibroblast Dynamics in Keloid Pathogenesis: Unraveling Cellular Crosstalk and Novel Therapeutic Targets

Keloid scars represent a complex fibroproliferative disorder characterized by abnormal wound healing and excessive collagen deposition. Central to keloid pathogenesis are dynamic fibroblast populations that undergo extensive phenotypic transitions, including heterogeneous subpopulation differentiation, enhanced migration, myofibroblast transdifferentiation, and sustained activation states. This review examines fibroblast dynamics as the central orchestrator of keloid formation, analyzing how these cells interact with keratinocytes, immune cells, endothelial cells, and melanocytes to drive pathological scarring. We focus on key signaling pathways that directly regulate fibroblast function, including TGF-β/Smad, VEGF, Wnt, and emerging regulators such as miR-3606-3p that integrate multiple fibrotic cascades. Current therapeutic approaches show variable efficacy, with surgical excision alone resulting in 45%-100% recurrence rates, while combination therapies incorporating radiation, intralesional injections, and novel molecular targets achieve improved outcomes. Emerging strategies include COX-2 inhibition for dual antiproliferative and proapoptotic effects on keloid fibroblasts, stem cell therapies, and precision medicine approaches based on molecular profiling. Through deeper understanding of fibroblast dynamics and their regulatory networks, more effective therapeutic strategies can be developed to improve patient outcomes and quality of life.