Circadian dysregulation of voltage-gated ion channels orchestrates cross-organ electrophysiological remodeling and therapeutic timing.

Disruption of intrinsic circadian rhythms alters cellular electrophysiology, promoting disease across multiple organ systems. We show that dysregulation of core clock genes (BMAL1, CLOCK, PER, CRY) remodels voltage-gated ion-channel (VGIC) expression, leading to sustained depolarization, impaired repolarization, and oxidative stress, unifying malignant and degenerative phenotypes. Integrative transcriptomic analysis across multi-organ datasets (GSE130408, GSE62944, TCGA-BRCA, TCGA-LAML, GSE56473) revealed consistent signatures: upregulation of sodium channels (SCN family), suppression of potassium channels (KCNQ, KCNH), and membrane potential drift toward -45 mV. In neuronal simulations, Vm shifted from -63 to -50 mV with a 2.3-fold ROS increase and firing rates rising from 2.5 to 6.7 Hz, reproducing seizure-like hyperexcitability. Retinal photoreceptors (rd10) depolarized from -65 to -47 mV, with a doubled burst index, indicating stress. In cardiac models and MEA-validated human iPSC-cardiomyocytes, SCN5A upregulation and KCNQ1/KCNH2 suppression prolonged action-potential duration by ∼35% and generated circadian oscillations in beat rate and field-potential duration, accurately predicted by a phase-aware LSTM network (r = 0.86 for BPM, r = 0.79 for FPD). In hematologic tissue, Gardos-channel impairment and TF/PAI-1 overexpression disrupted ROS-ATP coupling, accelerating leukemogenic and prothrombotic signaling. The LSTM model, trained on circadian multi-omic trajectories, predicted VGIC remodeling and cell-cycle transitions with >85% accuracy. Validation against published datasets via reanalysis in synchronized cell systems (MCF-10A → MDA-MB-231, U2OS, OCI-AML3) showed that NaV blockers (tetrodotoxin, lidocaine) or K+ openers (retigabine) restored rhythmicity, reduced ROS by ∼40%, and lowered proliferation by ∼35%. This integrative circadian-electrophysiological framework highlights tissue-specific trends in VGIC remodeling and suggests potential circadian-informed therapeutic strategies. While phase-dependent effects are supported in neuronal, retinal, and cardiac models, predictions for other organs remain inferred from transcriptomic data and require further experimental validation.