ROS-induced voltage-gated ion channel expression and electrophysiological remodeling in malignant human cells

Environmental stressors such as radiation, pH shifts, temperature variations, and electromagnetic fields can trigger intracellular oxidative stress, upregulating voltage-gated ion channel (VGIC) gene expression. This paper presents a hybrid modeling framework integrating Hodgkin-Huxley-based electrophysiological simulations with redox-sensitive transcriptional feedback to investigate how reactive oxygen species (ROS) modulate calcium signaling and drive electrophysiological reprogramming. In healthy epithelial cells (MCF-10A), sustained oxidative perturbations induce non-voltage-gated calcium influx, mitochondrial ROS generation, and VGIC transcription, shifting membrane potential from non-excitable to excitable states. Repeated ROS or thermal pulses promote progressive VGIC expression, depolarization, mRNA accumulation, and genomic instability. A Transformer-Long Short-Term Memory (LSTM) model, trained on simulated ROS-VGIC-V_m-mutation trajectories and human datasets (GSE45827), achieved >90% accuracy in predicting tumorigenic transformation. This framework enables simulation-guided drug target identification, ion channel parameter optimization, and AI-assisted screening of VGIC-modulating compounds, bridging systems biology with predictive oncology and informing electrophysiology-based therapeutic design.