Keratinocyte transport of notoginsenoside R1 via ABCG2: A novel mechanism for RNA N6-methyladenosine modification in UVB induced skin sunburn injury.

UVB radiation, a major environmental carcinogen, induces cyclobutane pyrimidine dimers and contributes to the development of squamous cell carcinoma. The RNA N6-methyladenosine modification (m6A) plays a critical role in regulating the DNA damage response. This study demonstrates that notoginsenoside R1 (NGR1), a bioactive ginsenoside derived from Panax notoginseng, protects against UVB induced skin sunburn injury. ABCG2 was identified as a key epidermal transporter responsible for the efflux of NGR1 from keratinocytes, revealing a previously unrecognized function of this efflux pump: the capacity to mediate the nonspecific import of NGR1. Mechanistically, NGR1 significantly upregulated WTAP expression, enhanced global m6A levels, and activated the m6A/DDB2 axis, resulting in a substantial reduction in cyclobutane pyrimidine dimers. These findings elucidate a molecular pathway through which NGR1, via ABCG2 mediated transport, mitigates UVB induced DNA damage responses by promoting m6A dependent DNA repair, positioning it as a promising candidate for topical therapeutic intervention. SIGNIFICANCE STATEMENT: Mechanisms by which NGR1 alleviates UVB induced skin sunburn injury via the WTAP/m6A axis and ABCG2 mediated trafficking offer a promising avenue for developing improved epidermal therapeutics for the related skin disorders.