Role of APE1 redox function in chronic rhinosinusitis pathogenesis: Implications for targeted therapy

Background: APE1 is a multifunctional enzyme with 2 distinct functions-endonuclease activity in its C-terminal domain and redox function in its N-terminal domain. The redox activity of APE1 regulates a subset of transcription factors involved in cell survival, angiogenesis, and inflammation. However, its role in chronic rhinosinusitis (CRS) with nasal polyps is not fully understood.

Objective: We sought to elucidate the role of APE1 redox function in the pathogenesis of CRS and to evaluate the therapeutic potential of targeting APE1 with redox inhibitors.

Methods: APE1 expression and function were assessed in human nasal tissues using single-cell RNA Sequencing, immunohistochemistry, Western blot, and quantitative RT-PCR. CRS mouse model, air-liquid interface-cultured human nasal epithelial cells, and BEAS-2B cells were used to examine the impact of the APE1 redox inhibitor on type 2 immune responses, mucus hypersecretion, epithelial barrier disruption, and oxidative stress.

Results: APE1 is highly expressed in patients with CRS with nasal polyps, and this upregulation was closely associated with eosinophil infiltration, mucus hypersecretion, epithelial damage, and oxidative stress. In the CRS mouse model and air-liquid interface-cultured human nasal epithelial cells, pharmacologic inhibition of APE1 redox function by C10 markedly reduced IL-25 production in tuft cells and decreased levels of type 2 cytokines (IL-4, IL-5, IL-13) along with T_H2 cell and group 2 innate lymphoid cell infiltration. Transcriptome analysis and in vitro experiments demonstrate that targeting APE1 effectively mitigates Reactive Oxygen Species generation, oxidative stress imbalance, and mitochondrial damage.

Conclusion: The findings underscore the potential role of APE1 redox function in CRS pathophysiology, particularly in driving type 2 inflammation, mitochondrial oxidative stress, mucus production, and epithelial barrier dysfunction. The APE1 redox inhibitor, C10, effectively blocked type 2 inflammation and improved CRS pathology, suggesting its therapeutic potential for CRS treatment.

APE1; APE1 redox inhibitor; C10; IL-25; chronic rhinosinusitis; oxidative stress disorder; tuft cell; type 2 inflammation.