Repurposing approved drugs as Pendrin (SLC26A4) inhibitors in allergic asthma: single-cell nomination, structure-based screening and functional validation.

Type-2 airway inflammation remodels the airway epithelium and drives mucus-associated transcriptional programs, making the epithelium an attractive source of drug targets in allergic asthma. Reanalyzing GSE193816, a lower-airway single-cell RNA-seq dataset of allergic asthma (AA) and allergic non-asthma control (AC) participants sampled before and after allergen challenge, a systematic epithelial prioritization ranked SLC26A4/Pendrin highly among asthma-enriched candidates, consistent with its previously reported induction in asthmatic airway epithelium. SLC26A4 was epithelial-biased, was strongest in allergen-challenged asthmatic epithelium, and co-varied with an IL-13/mucus program. Building on this nomination, structure-based virtual screening of approved drugs against the niflumic-acid inhibitor pocket of the cryo-EM Pendrin structure (PDB 8SHC) prioritized six chemically diverse, asthma-unrelated candidates predicted to occupy the pocket. In a halide-flux assay using cells co-expressing Pendrin and a halide-sensitive YFP reporter, these drugs produced concentration-dependent, partial inhibition of Pendrin-mediated transport, with deferasirox and lemborexant the most efficacious and exceeding the niflumic-acid positive control. Because inhibition was partial and occurred at high-micromolar concentrations, these data are a preliminary in vitro observation, consistent with but not confirming a repurposing hypothesis for Pendrin in allergic asthma, rather than evidence of therapeutic benefit.