Red light promotes dermis-epidermis remodeling via TGFβ and AKT-mediated collagen dynamics in naturally aging mice

Red light therapy is a clinically validated, noninvasive approach for improving skin structure and stimulating collagen renewal. However, the molecular mechanisms by which light therapy reverses collagen-related skin degeneration remain unclear. Using a natural aging mouse model, this study investigated the effects of red light therapy on skin structure and regeneration. Unlike other wavelengths, red light rapidly increased dermal thickness and stimulated epidermal renewal by enhancing collagen synthesis in dermal fibroblasts and activating collagen/integrin-induced proliferation and differentiation of epidermal keratinocytes, resulting in significant improvements in skin morphology. Mechanistically, red light increased endogenous TGFβ expression in fibroblasts, which up-regulated type I collagen mRNA and protein expression via activation of SMAD2/3/4 nuclear translocation. Simultaneously, red light elevated intracellular cAMP, triggering AKT activation that inhibited matrix metalloproteinase expression via the NFR2/HO-1-dependent pathway, thereby reducing collagen degradation. The accumulation of type I collagen in dermal fibroblasts stimulated integrin signaling, promoting epidermal keratinocyte proliferation and differentiation. Red light-induced AKT activation also enhanced fibroblast proliferation, further amplifying collagen production and collagen-mediated epidermal renewal. These findings elucidate the mechanisms by which red light stimulates endogenous TGFβ and AKT signaling to regulate type I collagen production, driving coordinated dermis-epidermis remodeling. This pathway represents a potential therapeutic target for the prevention and treatment of age-related dermal degeneration.