Targeting Anion Channels and Associated Epithelial Ion Channels in Health and Disease: TMEM16/Anoctamins, ENaC, VRAC, and Beyond

The TMEM16/anoctamin family, including ANO1, ANO2, ANO6, and ANO10, is increasingly recognized as a pharmacologically tractable class of proteins with calcium-activated chloride channel and/or phospholipid scramblase functions and important roles in cellular excitability, epithelial transport, smooth muscle function, sensory signaling, and disease-associated remodeling. Other chloride channels and chloride transport pathways, including the cystic fibrosis transmembrane conductance regulator (CFTR), the epithelial anion transporter SLC26A9, and the volume-regulated anion channel (VRAC/LRRC8), as well as the epithelial sodium channel (ENaC), whose activity is functionally coupled to chloride transport across epithelia, share overlapping physiological territory and therapeutic relevance, from epithelial fluid and electrolyte homeostasis to cell volume regulation and osmotic signaling. Translation of this broader chloride transport biology into therapeutic strategies remains limited by incomplete disease-context mechanisms, insufficiently selective pharmacological tools, unresolved channel-versus-scramblase or channel-versus-transporter functions, and fragmented preclinical validation. This Research Topic aims to consolidate recent mechanistic and translational advances across TMEM16/CaCC, CFTR, SLC26A9, VRAC, and other chloride channels and transport pathways, with a particular focus on target biology, chemical modulation, disease relevance, and drug discovery. We seek contributions that define the function of chloride channels, transporters, and related ion transport pathways in normal physiology and disease, develop or characterize modulators, degraders, natural products, or biological tools, including those addressing selectivity across paralogs and channel classes, validate target engagement and therapeutic efficacy in relevant models, and establish strategies to improve selectivity, safety, and clinical tractability.TMEM16/anoctamin proteins function as calcium-activated chloride channels, phospholipid scramblases, or both, depending on the family member, and are involved in diverse physiological processes, including epithelial secretion, smooth muscle contraction, neuronal and sensory signaling, and cell proliferation. CFTR and SLC26A9 contribute to epithelial chloride transport and fluid homeostasis, while VRAC mediates regulatory volume decrease and has emerging roles in glial and neuronal signaling and osmotic stress responses. ENaC governs sodium reabsorption across epithelia in the kidney, lung, and colon, with transport activity closely tied to parallel chloride conductance. Dysregulated activity across these channels and transport pathways has been implicated in cancer progression, inflammatory and epithelial disorders (including cystic fibrosis, IBD, asthma, and pancreatitis), gastrointestinal and airway dysfunction, pain, cardiovascular-related pathophysiology, and cell volume homeostasis. Recent advances in channel structure, electrophysiology, chemical biology, high-throughput screening, natural product pharmacology, and disease modeling have expanded the therapeutic potential of this broader class. Disease-specific mechanisms, channel-dependent versus non-channel functions, cross-family pharmacological selectivity, and in vivo translational relevance remain major challenges, making a Research Topic framed across chloride channels and transport pathways timely for integrating current knowledge and guiding future therapeutic development.This Research Topic welcomes manuscripts addressing TMEM16/CaCC, CFTR, SLC26A9, VRAC, ENaC, and related ion transport pathways and pharmacology across molecular, cellular, disease, and translational levels. Specific themes include, but are not limited to:• Channel structure and gating• Calcium-, voltage-, volume-, phosphorylation-, and ligand-dependent regulation• Comparative and paralog-selective pharmacology across channel families• Disease-specific mechanisms in cancer, inflammation, epithelial transport, smooth muscle, pain, blood pressure regulation, and cardiopulmonary or gastrointestinal disorders• Discovery and optimization of selective modulators and natural products• Targeted degradation strategies• Assay development, electrophysiology, and imaging• Target engagement and omics-based mechanism-of-action studies• Biomarkers and combination therapy• Resistance models and ADME-toxicity profiling• In vivo proof-of-concept studies Topic editors: Yohan Seo, JooHan Woo, Astrid Grosche Source: https://www.frontiersin.org/research-topics/82237/targeting-anion-channels-and-associated-epithelial-ion-channels-in-health-and-disease-tmem16anoctamins-enac-vrac-and-beyond