The gastrointestinal KATP-ERK signaling axis: Molecular mechanisms, pharmacological opportunities, and emerging translational technologies

Background ATP-sensitive potassium channels are metabolic sensors that couple intracellular nucleotide availability to membrane excitability, calcium signaling, mitochondrial function, and cell survival. Growing evidence identifies K ATP channels as essential regulators of gastrointestinal physiology. They are expressed in smooth muscle, enteric neurons, interstitial cells of Cajal, epithelial and enteroendocrine cells, microvascular cells, pericytes, and liver, where they contribute to motility, secretion, barrier integrity, nutrient sensing, vascular regulation, and mucosal protection. In parallel, ERK1/2 are central effectors of the MAPK pathway, controlling epithelial renewal, inflammation, fibrosis, apoptosis, and tissue repair. This review proposes an integrated K ATP -ERK signaling network that regulates gastrointestinal homeostasis. Methods PubMed and Scopus were searched for relevant studies using combinations of the terms “ERK” AND “K ATP channels” AND “cardiovascular” OR “gastrointestinal”. Results Evidence supports functional crosstalk between K ATP channels and ERK signaling. In this framework, K ATP channels act as metabolic rheostats, whereas ERK integrates redox, growth factor, and stress-related signals. Acute K ATP activation promotes adaptation by preserving mitochondrial function and epithelial barrier integrity, whereas chronic channel overactivation, as observed in Cantú syndrome caused by gain-of-function mutations in ABCC9 or KCNJ8 , may induce maladaptive remodeling, tight junction disruption, apoptosis, fibrosis, and dysmotility. The potential involvement of FGFR/Klotho signaling as an upstream ERK regulator, together with K ATP /ERK pharmacological modulation, FGF/Klotho-based therapies, and biosensor technologies for pathway monitoring in organoids and gut-on-chip models, is also discussed. Conclusions The K ATP -ERK-FGFR/Klotho framework links ion-channel pharmacology with gastrointestinal biology, providing a foundation for biomarker discovery, therapeutic development, and precision medicine approaches in gastrointestinal disorders.