Dysregulation of fatty acid and sphingolipid metabolism is involved in abnormal nasal epithelial differentiation

INTRODUCTION: Aberrant epithelial remodeling, driven by a shift from ciliated to goblet cell ratio, is central to chronic nasal inflammation. Despite the known role of metabolism in normal epithelial differentiation, the specific metabolic reprogramming patterns underlying this pathological shift of nasal epithelium induced by type 2 inflammatory milieu is poorly understood. This study aimed to delineate the key metabolic pathways involved in aberrant nasal epithelial differentiation. METHODS: We employed a human apical-out nasal organoid (hANO) model stimulated with IL-13. Integrated transcriptomic (RNA-seq) and untargeted metabolomic profiling was performed at undifferentiated (Day 0), mid- (Day 7), and mature (Day 18) differentiation stages. RESULTS: The IL-13-induced hANO model successfully recapitulated the aberrant differentiation phenotype of nasal epithelium. Multi-omics analyses converged to identify lipid metabolism as the most significantly altered functional module. Specifically, aberrant differentiation featured a reprogramming of fatty acid metabolism, marked by upregulated genes for uptake and elongation (CD36, ELOVL1/5/7), downregulated β-oxidation enzymes (ACADL, ACAA2), reduced acylcarnitines, and consequent free fatty acid accumulation. This was coupled with a distinct sphingolipid signature: while de novosynthesis was constrained and the sphingomyelinase pathway suppressed, the salvage synthesis pathway was specifically and persistently activated, evidenced by upregulation of key enzymes (CERS3/5, SGPP1/2) and elevated sphingosine, culminating in increased ceramide (e.g., C16:0) levels. CONCLUSION: Our work elucidates a time resolved lipid metabolic program, from fatty acid anabolism to dysregulated sphingolipid salvage synthesis, as a hallmark of aberrant nasal epithelial differentiation. This metabolic signature provides a novel framework for understanding epithelial remodeling in type 2 inflammation.