Background: RNA-binding proteins (RBPs) and ferroptosis have been demonstrated to play important roles in the progression of chronic rhinosinusitis (CRS). However, the regulatory mechanisms underlying the interaction between RBPs and ferroptosis in CRS, particularly regarding mitochondrial metabolism, remain elusive.
Methods: Hub genes correlated with RBP-related genes, ferroptosis-related genes and mitochondrial-related genes were identified by integrated bioinformatics analysis. CRS in vivo models were constructed, clinical samples were collected, and mechanistic analyses were performed for validation.
Results: ZFP36L1 was identified as the hub gene associated with CRS development. In vivo experiments demonstrated that ZFP36L1 directly binds to the 3′-untranslated region of CAMK2A mRNA and promotes its degradation through AU-rich element recognition. ZFP36L1 knockout in CRS mouse models restored CAMK2A expression and significantly attenuated ferroptosis markers, reactive oxygen species accumulation and mitochondrial dysfunction. Rescue experiments revealed that CAMK2A knockdown reversed the protective effects of ZFP36L1 depletion on ferroptosis and mitochondrial quality control. Clinical samples confirmed that ZFP36L1 expression was inversely correlated with CAMK2A levels, and both were associated with disease severity.
Conclusion: This study identifies ZFP36L1–CAMK2A as a contributory regulatory mechanism in CRS pathogenesis. ZFP36L1 promotes ferroptosis by destabilizing CAMK2A mRNA, leading to mitochondrial dysfunction and subsequent epithelial cell death. These findings provide new mechanistic insights into CRS progression and identify potential therapeutic targets.
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2026 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
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