HPV11 targeting KDM4A regulates the polarization of macrophage M1 and promotes the development of nasal inverted papilloma

Abstract The development of nasal inverted papilloma (NIP) is closely related to human papillomavirus (HPV) infection. Previous studies indicated that HPV11 shows the highest expression in NIP tissues. However, the mechanisms following its integration into host DNA require further clarification. In this study, high-throughput sequencing was employed to identify the HPV integration site KDM4A in HPV-positive specimens. The HPV11E6/E7 overexpression model was established in human nasal mucosal epithelial cells (HNE-pC), and the KDM4A gene was knocked out using CRISPR/Cas9 technology. Cell proliferation was assessed via CCK-8, colony formation, and EdU assays, while cell migration was evaluated through Transwell and wound healing assays. qRT-PCR and Western blot were used not only to analyze mRNA and protein expression in cells after HPV11E6/E7 overexpression and knockout of KDM4A but also to study the effect of the polarization of macrophages. A subcutaneous tumor model in nude mice validated the effects on proliferation and KDM4A knockout in vivo, with macrophage polarization types assessed via immunofluorescence staining. Results showed that HPV11E6/E7 overexpression significantly enhanced nasal epithelial cell proliferation and migration, along with promoting M1 macrophage polarization. Knockout of KDM4A inhibited these effects and delayed the progression of macrophages toward M1 polarization. Our findings suggest that low-risk HPV11 can drive the proliferation of nasal mucosa and regulate M1 macrophage polarization via KDM4A, potentially contributing to NIP pathogenesis. Targeting inhibition of KDM4A expression may represent a viable therapeutic strategy for HPV-positive NIP.