Multi-omics profiling identifies IL-13 signaling as a key mediator in Dupilumab-associated severe corneal injury

Objective To explore the epidemiological profile of Dupilumab-associated severe corneal injury (DASCI) using large-scale real-world evidence, and to investigate its underlying molecular mechanisms through integrated single-cell transcriptomic and network analysis. Methods A retrospective pharmacovigilance analysis focusing on Dupilumab was carried out utilizing the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database, covering data from first quarter of 2022 to the third quarter of 2025 (Q1 2022 to Q3 2025). A disproportionality analysis was conducted to quantify safety signals using the Reporting Odds Ratio (ROR) and Information Component (IC), with Upadacitinib and Tralokinumab serving as active comparators to strengthen the findings. The molecular mechanisms underlying Dupilumab's effects were investigated by performing single-cell RNA sequencing on human ocular surface cells, supplemented by protein-protein interaction (PPI) network analysis and Gene Ontology (GO) enrichment analysis. Results A total of 817 cases of DASCI identified from Q1 2022 to Q3 2025 exhibited a distinct epidemiological profile, characterized by an upward temporal trend, female predominance, and peak incidence among working-age and middle-aged adults. Severity assessment indicated that the majority of reported cases (74.4%) were classified as "medically significant," while an additional 19.7% required hospitalization. Time-to-event analysis revealed rapid disease progression, with median times of 38 days from initiation to mild conjunctivitis and 57 days to severe corneal damage. Disproportionality analysis confirmed a drug-specific risk signal for Dupilumab, which was absent for Upadacitinib; in contrast, Tralokinumab exhibited an even stronger signal. Single-cell transcriptomics delineated a compartmentalized IL-13 signaling network across the human ocular surface, highlighting critical roles of limbal epithelial cells, goblet cells, and macrophages. Subsequent PPI and GO enrichment analyses further established signal transducer and activator of transcription 6 (STAT6) as the central hub of this network. Furthermore, immunological reprogramming toward a Th2-to-Th1 shift may contribute to DASCI pathogenesis. Conclusion Dupilumab constitutes a significant risk factor for severe corneal injury, characterized by distinct pharmacoepidemiological and rapid progression features. Mechanistically, DASCI is triggered by IL-13 pathway blockade, mediated through a STAT6-centered network, and driven by a pathological Th2-to-Th1 shift.