Blue Light (λ = 453 nm) Significantly Reduces TGF-β-Induced Fibroblast Differentiation Through Reversible Disruption of Mitochondrial Respiration, Glycolysis, and ATP Production Rate

Background/Objectives: Abnormal differentiation of human skin fibroblasts into myofibroblasts contributes to fibrotic skin disorders such as hypertrophic scars, keloids, and Dupuytren’s disease. This process is characterized by increased fibroblast proliferation, enhanced differentiation into myofibroblasts, and reduced programmed cell death (apoptosis). We previously demonstrated that blue light irradiation (λ = 453 nm) significantly and dose-dependently inhibits both spontaneous and TGF-β-induced fibroblast differentiation. Methods: Because fibroblast differentiation depends on cellular energy metabolism, we investigated whether the inhibitory effect of blue light is linked to changes in the cells’ energy balance. Results: We found that blue light reduced TGF-β-induced differentiation, as shown by decreased levels of α-SMA and EDA-fibronectin, key markers of myofibroblast formation. This effect was strongly associated with almost complete inhibition of mitochondrial respiration, reduced glycolysis, a lower NAD⁺/NADH ratio, and decreased ATP production. ATP-dependent processes, including endocytosis and lysosomal activity, both essential parameters of fibroblast differentiation, were also strongly suppressed. Importantly, all these changes were fully reversible within 24 h after the last irradiation. Conclusions: Mechanistically, we propose that blue light triggers photochemical reduction in flavins in proteins of the respiratory chain and possibly the Krebs cycle, which temporarily alters cellular energy metabolism. These findings suggest that non-toxic blue light therapy (80 J/cm²) can effectively prevent factor-induced fibroblast differentiation and may serve as a standalone or supportive treatment to reduce fibrotic events such as scarring and keloid formation. Furthermore, our results indicate that targeting cellular energy metabolism, whether physically or pharmacologically, could be a promising strategy to prevent sclerotic skin disorders.