Pathology-Guided In Silico Electrophysiological Assessment of Amiodarone-Mediated Kv10.1 Inhibition in Breast Cancer

PURPOSE Kv10.1 (ether-à-go-go-1/Eag1) potassium channels are highly expressed in several malignancies, including breast cancer, where they contribute to tumor progression, enhanced proliferation, and aggressive pathological behavior. Increased Kv10.1 activity has been associated with membrane hyperpolarization, altered cellular excitability, lymphovascular invasion, and reduced patient survival. Amiodarone, a clinically approved antiarrhythmic agent, has demonstrated potent inhibitory effects on Kv10.1 channels and may represent a promising repurposed therapeutic candidate for ion channel–targeted cancer treatment. This study aimed to develop a pathology-oriented in silico electrophysiological framework to investigate the effects of amiodarone-mediated Kv10.1 inhibition on breast cancer membrane excitability, ionic conductance, and electrical signaling. METHODS A computational digital twin model of breast cancer electrophysiology was constructed incorporating Kv10.1-dominated outward potassium currents together with voltage-gated sodium and calcium conductances. Voltage-clamp simulations were performed across membrane potentials from −80 mV to +40 mV using 10 mV increments and 200 ms pulse durations to evaluate current–voltage characteristics and channel conductance. Current-clamp protocols applied injected currents ranging from −200 pA to +500 pA to assess resting membrane potential, excitation threshold, and spontaneous firing activity. Amiodarone inhibition was modeled as a 75% reduction in maximal Kv10.1 conductance based on reported pharmacological data. Simulations were conducted in a heterogeneous virtual cohort of 100 breast cancer cells representing distinct electrophysiological phenotypes. RESULTS Baseline simulations demonstrated strong Kv10.1-mediated outward currents reaching +28.4 pA/pF at +20 mV with maximal conductance of 12.5 pS/pF. Simulated amiodarone treatment reduced peak outward current to +7.6 pA/pF and decreased conductance to 3.4 pS/pF, producing a significant leftward shift in the current–voltage relationship. Resting membrane potential changed from −28.6 mV to −42.3 mV following Kv10.1 blockade. Action potential threshold increased, while spontaneous firing frequency decreased markedly from 4.2 Hz to 0.8 Hz. Cells exhibiting higher baseline Kv10.1 activity showed the greatest suppression of electrical activity. CONCLUSION Amiodarone markedly suppresses breast cancer electrophysiological activity through Kv10.1 inhibition in a pathology-informed digital twin model. These findings support the translational potential of Kv10.1-targeted ion channel modulation as a precision therapeutic strategy in breast cancer.