Multi-Omics and Molecular Docking Studies on Caffeine for Its Skin Rejuvenating Potentials.

Background: Caffeine (CA) exhibits promising reparative effects against UV-induced skin aging, but the specific mechanisms, including differences in gene and metabolite regulation and the involvement of signaling pathways, are still insufficiently elucidated. Methods: This study is on the repairing capability of CA to ultraviolet (UV)-induced skin aging and explores the ferroptosis pathway through in vitro cell experiments, a UV-aged mouse skin model, and molecular docking. Results: CA enhanced the vitality and proliferation of HaCaT cells, delayed cell aging, reduced reactive oxygen species levels, increased mitochondrial membrane potential, and activated the peroxisome proliferator-activated receptor pathway, as well as repaired UVB-induced cytoskeletal disorders. Simultaneously, CA reduced other related but undesirable biological mechanisms. Moreover, multi-omics and network pharmacology studies suggested that CA mitigated aging by modulating related metabolic and ferroptosis pathways. Additionally, CA effectively reduced lipid peroxidation and intracellular ferrous ion levels and regulated the expression of key ferroptosis proteins, and its potential anti-aging effects were also confirmed through the modulation of ferroptosis pathways. In addition, molecular docking revealed strong interactions between CA and related key proteins, further supporting the potentiality of CA. Conclusions: This study elucidates the effectiveness and potential mechanism of CA to reduce the UV-induced skin aging.