Altered Potassium Channels in Pancreatic Ductal Adenocarcinoma: Mechanisms, Implications, and Therapeutic Opportunities

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies, characterized by late diagnosis, aggressive metastatic behavior, and profound resistance to current therapies. Ion channels are increasingly recognized as active participants in oncogenesis, challenging the historic view of cancer as solely a genetic and biochemical disease. Emerging evidence has established that potassium (K+) channels, a structurally and functionally diverse superfamily of ion-conducting proteins, are systematically dysregulated in PDAC and play active roles in virtually every hallmark of this cancer, including uncontrolled proliferation, resistance to apoptosis, enhanced cell migration and invasion, metabolic reprogramming, and immunosuppressive tumor microenvironment remodeling. Potassium channels deregulation form part of a major deregulation frame, that is the electrochemical network deregulation (ECND). ECND is a neglected player in PDAC that is just recently being recognized as an interesting opportunity for therapeutic interventions. Potassium channels play an important role in ECND because they participate directly or indirectly in all the main manifestations of ECND, that is intracellular alkalosis, extracellular acidosis, plasmatic and mitochondrial membranes voltage, ROS homeostasis, calcium ion signaling, and pseudosynapsis. The lack of success of all pharmacological treatments attempted so far compels us to explore new therapeutic avenues. The deregulation of the electrochemical network in cancer, and in particular of the potassium channels that are an integral part of this network, are poorly recognized and investigated potential targeting areas. Furthermore, there are existing and developing drugs in this regard. This review provides a comprehensive analysis of the major K+ channel families involved in PDAC: voltage-gated (Kv) channels, inward rectifier (Kir) channels, two-pore domain (K2P) channels, and calcium-activated (KCa) channels. We examine the molecular mechanisms by which each channel subfamily contributes to oncogenic signaling, discuss their crosstalk with key PDAC driver pathways including KRAS, PI3K/AKT, and Wnt/β-catenin, and evaluate their potential as diagnostic biomarkers and therapeutic targets. Special attention is paid to the pharmacological landscape, including repurposed drugs and novel channel-targeting strategies. Collectively, the literature supports a model in which K+ channel dysregulation is not an epiphenomenon but a mechanistically integral feature of PDAC physiopathology, warranting prioritized investigation in preclinical and clinical settings.