Systems Approaches to Unravel Molecular Function: High-content siRNA Screen Identifies TMEM16A Traffic Regulators as Potential Drug Targets for Cystic Fibrosis

•Some CF patients (∼20%) are not eligible for highly effective CFTR modulator drugs.•An attractive ‘by-pass’ therapy for CF is to stimulate non-CFTR chloride channels.•A high-content siRNA screen revealed 262 modulators of TMEM16A channel traffic.•Hit validation shows that ADRA2C and CXCR3 knock-down boosts TMEM16A Cl− secretion.•Inhibiting these two TMEM16A modulators is a potential therapeutic strategy for CF.