Regulatory mechanisms of transforming growth factor-β in senescence of fibroblast associated with refractory skin diseases

Fibroblasts, critical for skin structure and function via extracellular matrix (ECM) production, undergo senescence linked to ECM changes and inflammation via senescence-associated secretory phenotypes (SASPs). Transforming growth factor (TGF-β), a pleiotropic cytokine, modulates fibroblast function through multiple signaling pathways, inducing cell cycle arrest, oxidative stress, DNA damage, and SASP production. These processes disrupt ECM homeostasis, exacerbate inflammation, and impair tissue repair, contributing to pathological skin changes. TGF-β induced fibroblast senescence involves multiple mechanisms and pathways. It causes cell cycle arrest by upregulating CDK inhibitors and activating the p53 pathway. TGF-β also promotes oxidative stress-induced senescence by increasing reactive oxygen species (ROS) production, activating pathways like SMAD, and causing DNA damage. In photoaging, UV exposure induces fibroblast senescence via TGF-β related mechanisms, reducing collagen production and increasing MMP levels. TGF-β also suppresses immune cell functions, creating an immunosuppressive microenvironment that accelerates cellular senescence. In refractory skin diseases like vitiligo, melanoma, and so on, TGF-β plays a complex role. Its abnormal activation drives fibroblast senescence, impacting immune responses and skin structure. However, Maintaining the normal expression of TGF-β preserves ECM homeostasis, promotes collagen synthesis, and reduces inflammatory factor expression. Emerging therapeutic strategies targeting TGF-β signaling show promise. Pharmaceutical agents and phototherapy mitigate senescence by modulating TGF-β pathways and thus suppress ROS, enhancing collagen synthesis. Combined approaches synergistically improve skin repair and elasticity. In summary, TGF-β significantly regulates fibroblast senescence in refractory skin diseases through various mechanisms and pathways. Its precise modulation could enhance skin repair and anti-aging therapies. However, further research is needed to explore the interactions between anti-aging ingredients and their clinical effects. • TGF-β affects cell proliferation, apoptosis and migration through pathways such as regulating the cell cycle, oxidative stress and DNA damage, thereby leading to fibroblast senescence. When the function of immune cells is inhibited, it will accelerate cell aging and form an inflammatory amplification cycle. In the meanwhile, TGF-β also participating in photoaging and affecting the health status of the skin. • In refractory skin diseases, such as vitiligo, the decreased level of TGF-β will aggravate inflammation and tissue damage. Besides, TGF-β has a significant impact on the disease development process.In melanoma, TGF-β can promote the invasion and migration of tumor cells. In psoriasis and systemic lupus erythematosus, TGF-β affects the cell cycle, promotes collagen synthesis and the expression of inflammatory factors, and has a significant impact on the disease development process. • Anti-aging treatment methods targeting the TGF-β signaling pathway have potential. Means such as drugs and phototherapy can regulate the TGF-β signaling pathway, inhibit ROS generation, enhance collagen synthesis, improve skin repair and elasticity. However, further research is needed on the interactions and clinical effects among anti-aging components to achieve more precise treatment strategies.