This review explores the mechanisms of chronic radiation-induced skin injury fibrosis, focusing on the transition from acute radiation damage to a chronic fibrotic state. It examines the cellular and molecular responses of the skin to radiation, highlighting the role of myofibroblasts and the significant impact of Transforming Growth Factor-β (TGF-β) in promoting fibroblast-to-myofibroblast transformation. The review delves into the epigenetic regulation of fibrotic gene expression, the contribution of extracellular matrix proteins to the fibrotic microenvironment, and the regulation of the immune system in the context of fibrosis. It also discusses the potential of biomaterials and artificial intelligence in medical research to advance the understanding and treatment of radiation-induced skin fibrosis, suggesting future directions involving bioinformatics and personalized therapeutic strategies to enhance patient quality of life. Radiation therapy, a key treatment for cancer, can cause acute and chronic skin injuries. Acute radiation skin injury occurs in about 95% of patients, with some developing severe radiodermatitis. Chronic radiation skin injury involves persistent skin damage, leading to fibrosis, characterized by dryness, atrophy, and potential ulcers. Fibrosis negatively affects quality of life by causing physical symptoms and social withdrawal. Patients with severe fibrosis may need to avoid further radiotherapy. The progression of radiation skin injury involves initial damage, acute inflammation, and transition to chronic fibrosis. Myofibroblasts, key cells in fibrosis, originate from resident fibroblasts and epithelial/endothelial cells through EMT/EndMT. TGF-β plays a central role in fibrosis by promoting fibroblast activation and myofibroblast differentiation. TGF-β signaling pathways, including Smad, Wnt/β-catenin, MAPK, and PI3K/Akt, are crucial in fibrosis development. Epigenetic regulators such as microRNAs and DNA methylation also influence fibrotic gene expression. The fibrotic microenvironment is characterized by excessive collagen and fibronectin, contributing to a profibrotic environment. The immune system, including innate and adaptive immune cells, plays a significant role in fibrosis. Macrophages and T cells contribute to fibrosis through cytokine production and immune cell recruitment. Cytokines like TGF-β, IL-13, and IL-17 drive fibrosis progression. Therapeutic targeting of TGF-β and its downstream effectors, such as Smad proteins, presents a promising approach. Combination therapies involving TGF-β inhibitors and immune modulators may offer effective treatment strategies. Biomaterials and tissue engineering offer innovative approaches for skin regeneration, while computational biology and bioinformatics provide new insights into fibrosis mechanisms and personalized treatment options. These advancements hold promise for improving the management and treatment of radiation-induced skin fibrosis.This review explores the mechanisms of chronic radiation-induced skin injury fibrosis, focusing on the transition from acute radiation damage to a chronic fibrotic state. It examines the cellular and molecular responses of the skin to radiation, highlighting the role of myofibroblasts and the significant impact of Transforming Growth Factor-β (TGF-β) in promoting fibroblast-to-myofibroblast transformation. The review delves into the epigenetic regulation of fibrotic gene expression, the contribution of extracellular matrix proteins to the fibrotic microenvironment, and the regulation of the immune system in the context of fibrosis. It also discusses the potential of biomaterials and artificial intelligence in medical research to advance the understanding and treatment of radiation-induced skin fibrosis, suggesting future directions involving bioinformatics and personalized therapeutic strategies to enhance patient quality of life. Radiation therapy, a key treatment for cancer, can cause acute and chronic skin injuries. Acute radiation skin injury occurs in about 95% of patients, with some developing severe radiodermatitis. Chronic radiation skin injury involves persistent skin damage, leading to fibrosis, characterized by dryness, atrophy, and potential ulcers. Fibrosis negatively affects quality of life by causing physical symptoms and social withdrawal. Patients with severe fibrosis may need to avoid further radiotherapy. The progression of radiation skin injury involves initial damage, acute inflammation, and transition to chronic fibrosis. Myofibroblasts, key cells in fibrosis, originate from resident fibroblasts and epithelial/endothelial cells through EMT/EndMT. TGF-β plays a central role in fibrosis by promoting fibroblast activation and myofibroblast differentiation. TGF-β signaling pathways, including Smad, Wnt/β-catenin, MAPK, and PI3K/Akt, are crucial in fibrosis development. Epigenetic regulators such as microRNAs and DNA methylation also influence fibrotic gene expression. The fibrotic microenvironment is characterized by excessive collagen and fibronectin, contributing to a profibrotic environment. The immune system, including innate and adaptive immune cells, plays a significant role in fibrosis. Macrophages and T cells contribute to fibrosis through cytokine production and immune cell recruitment. Cytokines like TGF-β, IL-13, and IL-17 drive fibrosis progression. Therapeutic targeting of TGF-β and its downstream effectors, such as Smad proteins, presents a promising approach. Combination therapies involving TGF-β inhibitors and immune modulators may offer effective treatment strategies. Biomaterials and tissue engineering offer innovative approaches for skin regeneration, while computational biology and bioinformatics provide new insights into fibrosis mechanisms and personalized treatment options. These advancements hold promise for improving the management and treatment of radiation-induced skin fibrosis.