Skin photoaging caused by accumulated UV radiation manifests as uneven pigmentation, telangiectasia, rough texture, wrinkles, and loss of elasticity [1]. Beyond the cosmetic manifestations of photoaging, UV-induced DNA damage, cellular senescence, and reactive oxygen species (ROS)-mediated chronic inflammation contribute to the development of non-melanoma skin cancers, including basal cell carcinoma, actinic keratosis, and squamous cell carcinoma [2], [3]. Thus, developing strategies to mitigate UV-induced skin photoaging is crucial.

UV radiation can directly induce DNA damage, including telomere shortening, single-strand breaks, double-strand breaks (DSBs), and the formation of G-quadruplex DNA structures [4]. In addition, UV-induced ROS indirectly damage DNA by promoting oxidative stress and triggering the production of inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, as well as chemokines including CCL2 and CXCL2, which collectively constitute the senescence-associated secretory phenotype (SASP) [5], [6]. Persistent oxidative stress also impairs mitochondrial function, activating pro-apoptotic proteins Bax and Bak and decreasing levels of the anti-apoptotic protein BCL2, thereby exacerbating apoptosis [7]. DNA damage can be repaired by multiple pathways, such as homologous recombination repair (HRR), nucleotide excision repair (NER), and base excision repair (BER). Failure to repair damaged DNA results in the accumulation of genetic mutations and sustained genomic instability, ultimately promoting oncogenic transformation, particularly within a chronic inflammatory microenvironment [8]. DNA damage and oxidative stress are contributing to chronic inflammation and cellular senescence, which cause cell cycle arrest and apoptosis during photoaging [9], [10], [11], [12].

Ginkgetin (GK), a naturally occurring biflavonoid isolated from the leaves and seeds of Ginkgo biloba, exhibits a wide range of biological effects [13]. Extracts of Ginkgo biloba have been extensively investigated in age-related diseases, including macular degeneration, primary hypertension, and tardive dyskinesia [14], [15], [16]. Recent studies indicate that GK modulates matrix metalloproteinases (MMPs), ameliorates atherosclerosis through antioxidant effects, and alleviates chronic obstructive pulmonary disease by downregulating C/EBPβ and inhibiting inflammatory cytokines [17], [18]. Furthermore, GK has shown potential as a senolytic agent, underscoring its application in mitigating skin photoaging [19]. However, whether GK alleviates photoaging and age-related cellular senescence by modulating DNA damage remains unknown.

This study investigates the therapeutic effect and mechanisms of GK in treating skin photoaging. We demonstrated that GK attenuates UV-induced photoaging phenotypes in the SKH-1 hairless mouse model. Subsequently, transcriptomic analysis of the SKH-1 mouse model, network pharmacology data from public databases, and molecular experiments using UV-induced photoaged fibroblasts and keratinocytes showed that GK reverses cellular senescence by suppressing the SASP, inhibiting apoptosis, and enhancing cell cycle progression, which is achieved by reducing UV-induced ROS accumulation and promoting DNA damage repair via Protein kinase B (AKT)-mediated HRR. These findings suggest that GK may serve as a promising therapeutic agent for skin photoaging and skin cancer prevention.