UCHL1 Promotes M1 Macrophage Polarization and Inflammation in Chronic Rhinosinusitis by Stabilizing HIF-1α.

While the persistent inflammation in chronic rhinosinusitis (CRS) is closely linked to M1 macrophage polarization, the mechanisms that control this polarization have not been fully elucidated. A positive correlation was observed between UCHL1 (a significantly upregulated deubiquitinating enzyme in CRS tissues) and M1 macrophage markers in our bioinformatic analysis. Suppression of UCHL1, via genetic knockdown or pharmacologic inhibition (6RK73), attenuated M1 macrophage polarization and curtailed the production of IL‑1β, TNF‑α and IL‑6 in both cellular and animal models. Mechanistically, UCHL1 interacts with HIF‑1α and stabilizes it by deubiquitinating it, thereby blocking its proteasomal degradation. This stabilization is functionally relevant, as HIF‑1α activation reversed the suppression of M1 polarization induced by UCHL1 knockdown. Furthermore, conditioned medium from UCHL1‑deficient macrophages mitigated epithelial cell damage-an effect that was abolished by HIF‑1α agonism. In a murine CRS model, pharmacological inhibition of UCHL1 significantly ameliorated histopathological injury, reduced behavioral symptoms such as sneezing and nasal scratching, and lowered IgE levels, and pro‑inflammatory cytokines, while downregulating the UCHL1/HIF‑1α axis and M1 marker expression. Collectively, these findings indicate that UCHL1 drives M1 macrophage polarization and exacerbates CRS inflammation by stabilizing HIF‑1α through deubiquitination, highlighting UCHL1 as a potential therapeutic target in CRS.