Elevated EZH2 expression is associated with reduced NRF2-related antioxidant signaling and ferroptosis-associated features in eosinophilic chronic rhinosinusitis with nasal polyps

Recurrence remains common in eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP) despite surgery and type 2-directed therapy, suggesting that epithelial injury mechanisms beyond cytokine signaling remain incompletely defined. Epigenetic-redox dysregulation is a plausible contributor, but its relationship to NRF2-associated antioxidant defenses in eCRSwNP has received little attention. Current therapies suppress type 2 inflammation but may not directly address persistent epithelial redox imbalance, providing a rationale for examining complementary regulatory pathways in patients with severe recurrent disease. We explored associations among EZH2 expression, NRF2-related antioxidant readouts, oxidative injury, and ferroptosis-associated features using patient sinonasal tissues, primary nasal epithelial cells subjected to EZH2-targeting shRNA, and an exploratory AAV-treated mouse model. In human tissues, higher EZH2 expression accompanied lower NRF2-related antioxidant marker levels and a ferroptosis-associated expression pattern. In cultured cells, EZH2 targeting was accompanied by improved antioxidant readouts, lower intracellular oxidation, and less mitochondrial injury. The mouse experiment showed parallel treatment-associated differences in protein staining and sinonasal histopathology, although EZH2 target engagement in nasal mucosa was not confirmed. These findings do not establish ferroptosis because functional rescue, iron-dependence testing, and direct phospholipid-peroxidation measurements were not performed. They also do not establish NRF2 dependence, direct EZH2–NRF2 binding, or the temporal direction of the relationship among EZH2, NRF2-related readouts, and oxidative stress. The results therefore identify a preliminary epigenetic-redox association rather than a defined EZH2–NRF2 mechanism. This framework may help guide future studies incorporating time-resolved measurements, reciprocal genetic perturbation, NRF2 localization and activity assays, ferroptosis-selective rescue, and direct validation of in vivo target engagement.