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<p>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<sub>m</sub>–mutation trajectories and human datasets (GSE45827), achieved &gt;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.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月27日

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  • Mohammad Mohammadiaria

摘要

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–Vm–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.