Targeting TWEAK/Fn14 pathway: Implications for stem cell regulation and advancements in skin disease therapies.

Tumor necrosis factor-like weak apoptosis-inducing factor (TWEAK), a member of the TNF superfamily, plays a critical role in regulating numerous cellular processes, including proliferation, differentiation, and migration, through its sole receptor, fibroblast growth factor-inducible 14 (Fn14). This signaling pathway has broad implications in normal physiology and the pathogenesis of various diseases. In skin disorders, TWEAK/Fn14 signaling is implicated in fibroproliferation, angiogenesis, and inflammation. It is upregulated in the serum and urine of patients with conditions like lupus erythematosus, psoriasis, and skin tumors. On the one hand, moderate activation of this pathway promotes skin wound healing; on the other hand, prolonged or excessive activation may lead to pathological tissue damage. Beyond skin diseases, TWEAK/Fn14 signaling also influences the behavior of various stem cells, including liver, neural, and mesenchymal stem cells, modulating their proliferation and differentiation during tissue repair and regeneration. Given its diverse biological roles, this pathway holds potential as both a diagnostic biomarker for early disease detection and a therapeutic target for treating a range of conditions. This review examines the dual roles of TWEAK/Fn14 signaling in both skin disease pathogenesis and stem cell regulation, highlighting its potential to advance research in disease mechanisms, stem cell therapy, and tissue engineering.