Oroxylin A inhibits UVB-induced non-melanoma skin cancer by regulating XPA degradation

Objective: Skin cancer, especially non-melanoma skin cancer (NMSC), is the most common type of cancer worldwide, accounting for approximately 40% of all cancers. The incidence of skin cancer has increased significantly over the past few decades. Oroxylin A, a natural product extracted from Scutellaria baicalensis Georgi, has been reported to show multiple pharmacological activities. However, the effect of Oroxylin A on NMSC and the underlying mechanism remains unknown. Methods: SKH-1 hairless mice were used to assess the effect of Oroxylin A on UVB-induced skin damage and NMSC. qRT-PCR, slot blot and immunofluorescence staining were performed to test the influence of Oroxylin A on inflammation and photoproduct removal. The binding target of Oroxylin A was identified with mass spectra and the mechanism of Oroxylin A inhibiting UVB-induced non-melanoma skin cancer was clarified with western blot. Results: In the present study, we demonstrated that Oroxylin A postponed the occurrence of UVB-induced NMSC and alleviated UVB-induced acute skin damage. Our study elucidated the underlying mechanisms by which Oroxylin A mitigates UVB-induced skin inflammation and enhances DNA repair through maintaining the stabilization of XPA protein, a crucial component of nucleotide excision repair. By binding to GRP94, Oroxylin A inhibits MDM2-mediated XPA ubiquitination and subsequent degradation. Conclusions: Our findings revealed that Oroxylin A stabilizes XPA protein by affecting the binding of GRP94 and MDM2, thereby promoting NER, alleviating UVB-induced skin damage, and finally delaying the development of NMSC. Our findings demonstrate that Oroxylin A is a promising candidate drug for the prevention of NMSC.