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

Oroxylin A, a natural compound derived from Scutellaria baicalensis, shows preventive potential against UVB-induced non-melanoma skin cancer (NMSC), the most prevalent cancer globally with escalating incidence. Using SKH-1 hairless mice exposed to UVB, we demonstrated that oroxylin A delayed NMSC onset and mitigated acute skin damage. Mechanistic studies revealed its dual action: suppressing inflammation and enhancing nucleotide excision repair (NER) by stabilizing XPA, a core DNA repair protein. This stabilization occurred through oroxylin A’s binding to GRP94, which disrupted MDM2-mediated XPA ubiquitination and proteasomal degradation. By preserving XPA levels, oroxylin A accelerated photoproduct clearance and reduced genomic instability, ultimately impeding NMSC development. These findings position oroxylin A as a novel chemopreventive agent targeting the GRP94/MDM2-XPA axis to counteract UVB-induced carcinogenesis.