BACKGROUND: Ultraviolet (UV)-induced reactive oxygen species (ROS) production, DNA damage, and chronic inflammation lead to skin aging and cancers. Ginkgetin (GK), a biflavonoid derived from Ginkgo biloba, has known anti-inflammatory and antioxidant activities, but its anti-photoaging effect remains unclear.
OBJECTIVE: This study aimed to determine whether GK could alleviate UV-induced photoaging by reducing oxidative stress and promoting DNA repair.
METHODS: The efficacy of microneedle-assisted topical GK was evaluated in a UV-induced SKH-1 mouse model of photoaging using dermoscopy and histopathological analysis. We conducted transcriptomic profiling and network pharmacology to identify the underlying mechanism. In UV-irradiated human dermal fibroblasts (HDFs), cellular senescence markers were assessed by SA-β-gal staining and Western blotting. Intracellular ROS levels and mitochondrial membrane potential were measured using DCFH-DA and JC-1 staining, respectively. Apoptosis, cell cycle progression, and senescence-associated secretory phenotype (SASP)-related cytokine expression were analyzed by flow cytometry, Western blotting, RT-qPCR, and ELISA. DNA damage and repair in UV-irradiated HaCaT cells were evaluated by comet assay and γ-H2AX immunofluorescence. Homologous recombination repair (HRR)-related proteins and RAD51 foci formation were analyzed by Western blotting and confocal microscopy, respectively. Functional validation was performed using the AKT inhibitor MK2206 and the HRR inhibitor B02.
RESULTS: GK significantly reduced wrinkle formation, epidermal hyperplasia, and collagen loss in UV-induced mice. It decreased ROS levels, restored mitochondrial potential, reduced senescence markers, suppressed SASP cytokines and MMP1/2 expression, promoted cell cycle progression, and inhibited apoptosis by regulating the BCL2/BAX ratio. Importantly, GK enhanced DNA repair by promoting HRR, as directly demonstrated by the upregulation of key HRR proteins (BRCA2, RAD51) and the acceleration of RAD51 foci formation. Critically, these DNA repair-enhancing effects were abolished by inhibition of either AKT or HRR, demonstrating that the AKT-HRR axis is indispensable for GK's repair-promoting function.
CONCLUSION: GK may serve as a potential therapeutic candidate for UV-induced photoaging by virtue of its dual capacity to scavenge ROS and enhance AKT-mediated DNA repair.
