UCA1 drives epidermolytic ichthyosis pathogenesis via miR-125a sponging and STAT3 dysregulation

Summary: Abstract Body: Epidermolytic ichthyosis (EI) is a rare hereditary skin disorder characterized by scaling, erythema, and an impaired epidermal barrier. Our RNA-seq dataset from biopsied EI skin (GSE192832) was reanalyzed to identify long non-coding RNAs (lncRNAs) that regulate gene expression via microRNA sponging in EI. Among the identified lncRNAs, UCA1 exhibited the highest fold change (3.1-fold, p<0.0001), suggesting a potential regulatory role. We hypothesized that UCA1 suppresses miR-125a to increase STAT3 signaling, promoting inflammation and cell growth in EI, like its role in psoriasis. miR-125a inhibits STAT3 translation by binding its mRNA, while UCA1 sequesters miR-125a, enabling STAT3-driven inflammation and highlighting a key miR-125a/STAT3 axis in EI pathogenesis. Enrichment pathway analysis of miR-125a targets in RNAseq dataset revealed key processes, including immunomodulation, cell proliferation, and the EGFR signaling pathway in EI. Six skin biopsies from patients (15-61 years old) with KRT10 pathogenic variants were collected after IRB-approved consent. RNA and protein were extracted from keratinocytes (KCs) isolated from patient vs. matched controls to study the UCA1/miR-125a/STAT3 axis. qRT-PCR analysis confirmed increased UCA1 expression (2-fold; p<0.05) in EI KCs. TNFA, a STAT3 target gene, was increased in EI samples (1.67-fold, p<0.01), indicating a dysregulated inflammatory response. Additionally, potential STAT3 target genes, FOS (1.2-fold, p<0.05), CCND1 (2.3-fold, p<0.001), CTNNB1 (1.4-fold, p<0.001), and MYC (2-fold, p<0.001), all showed increased expression in EI KCs, suggesting a coordinated disruption of cell cycle regulation, differentiation balance, and inflammatory response. Western blot analysis showed increased total and phospho-STAT3 in EI KCs, linking UCA1 to STAT3 dysregulation in cultured KCs. Our findings indicated that UCA1 may modulate the miR-125a/STAT3 signaling axis in EI, leading to abnormal cell proliferation and inflammatory response, and suggesting a new therapeutic target. Zhengyi Lin¹, Lydia Rabbaa Khabbaz¹, Nihal Kaplan¹, Amy Paller¹ 1. Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States. Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics