Synergistic Effects of Retinol and Retinyl Palmitate in Alleviating UVB-Induced DNA Damage and Promoting the Homologous Recombination Repair in Keratinocytes

Ultraviolet B (UVB) rays are a type of ultraviolet radiation emitted by the sun, primarily responsible for skin photodamage. These rays mainly affect the epidermis, leading to direct damage to DNA and contributing to skin cancer development. Retinol and its derivatives are effective in combating skin aging and photodamage, but they often cause skin intolerance, limiting their use despite their potent effects. Therefore, investigating optimal compositions of retinoids is essential to enhance their efficacy against photodamage. In this study, we aimed to investigate the synergistic effects of retinol (ROL) and retinyl palmitate (RPalm) in alleviating UVB-induced DNA damage in human keratinocytes (HaCaT). Applying the ROL+RPalm combination after UVB exposure in HaCaT cells significantly reduced inflammation and apoptosis while promoting collagen synthesis compared to individual treatments with ROL or RPalm. Through bulk mRNA sequencing, we identified that the biological function of the ROL+RPalm synergy is primarily directed toward mediating DNA damage repair. Using comet assays, Western blotting, immunofluorescence, and flow cytometry, we demonstrated the anti-DNA damage effects of ROL+RPalm in HaCaT cells and reconstructed human epidermis. We further elucidated that the molecular mechanism underlying the ROL+RPalm combination involves the activation of RARβ, which subsequently triggers the ATM-CHK2-p53 signaling pathway and increases the expression of homologous recombination (HR)-associated repair genes. This combination presents a potential therapeutic strategy for UVB-induced photodamage and emphasizes the synergistic effects of ROL and RPalm in alleviating UVB-induced DNA damage.