Identification and validation of Novel Estrogen Biosynthesis Biomarkers in Sinonasal Inverted Papilloma

<b>Background:</b> Sinonasal inverted papilloma (SNIP) is characterized by a high recurrence rate and potential for malignant transformation. Although metabolic reprogramming plays a role in benign neoplasms, the specific metabolic pathways and biomarkers involved in SNIP pathogenesis remain unclear. <b>Methods:</b> RNA sequencing on paired SNIP and normal tissues identified altered genes with enzyme annotations and metabolic pathways by intersecting our cohort data (GSE270193, N=2) with the GSE193016 (N=4) dataset using Ingenuity Pathway Analysis. Functional and interaction assessments were performed using Metascape and STRING, with further validation via tissue microarray from an independent SNIP cohort (N=30). <b>Results:</b> The estrogen biosynthesis pathway was significantly altered in both datasets. Five key biomarkers, AKR1B10, CYP1B1, CYP2C19, CYP3A5, and HSD17B13, were significantly altered in SNIP tissues. These markers, sharing Gene Ontology terms, showed significant correlations at both the transcript and protein levels. Functional analysis revealed enrichment in epithelial cell proliferation and regulation of EGFR signaling, suggesting a role in SNIP pathogenesis. Validation in an independent cohort confirmed elevated protein levels of these markers, all positively correlated with EGFR in SNIP tissues. Notably, AKR1B10, CYP2C19, and CYP3A5 exhibited specific expression patterns distinguishing SNIP from sinonasal squamous cell carcinoma. <b>Conclusion:</b> Altered estrogen biosynthesis signaling plays a role in SNIP pathogenesis, revealing distinct biomarkers that could serve as novel diagnostic markers and therapeutic targets for SNIP management.