Bioelectrical signals in cells provide dynamic cues that determine function with the sodium ion (Na+) having pivotal roles. These include alterations to the mechanical properties and/or permeability of the cell membrane mediated in part by Na+ channels[MM1] . With developing paradigms of cancer as a chanelopathy, further understanding of altered ion channel homeostasis in ovarian cancer (OvCa) is essential. The aim of this study was to investigate the contribution to bioelectric gradients, altered expression and functional modulation of Na+ channel homeostasis on critical hallmarks of OvCa. Relative Na+/K+ permeability to evaluate contribution of Na+ to Vmem in the SKOV-3 OvCa cell line was investigated with the whole-cell current clamp (I=0) technique using ion substitution for Na+. The impact of Na+ channel inhibition on proliferation and cell cytotoxicity was assessed using resazurin (100µM) and sytox green (5µM) respectively in SKOV-3 and OVCAR3 (N=5) over 72h. Amiloride(0.1-100µM) and phenytoin (5-200µM) were used to inhibit ENaC and voltage gated sodium channels respectively. Migratory contribution of ENaC on was assessed through scratch assays in the presence of amiloride (1-100µM) (SKOV-3, N=3) over 48h. RT-qPCR of the α-ENaC subunit in conjunction with western-blotting to confirm protein expression was utilised to validate the presence in SKOV-3 and OVCAR-3 cells (N=3 RT-qPCR, N=4 western blot expts). In order to assess differential expression of ENaC in OvCa in human subjects, RT-qPCR was used to compare α-subunit levels between total ovarian homogenates from patients undergoing oophorectomy for a non-malignant condition (N=8) or tumour excision (stage 3, N=6). In SKOV-3 cells the relative Na+:K+ permeability ratio to Vmem was 1.94 ± 0.92 (mean±SD). Both amiloride and phenytoin significantly reduced the proliferative capacity of SKOV-3 (IC25 at 72hrs: amiloride = 30.8 [20.1-40.5], phenytoin = 105 [68.9-161.8]) and OVCAR3 (IC25 at 72hrs: amiloride = 33.9 [16.9-59], phenytoin = 221.8 [CI not determined]) cell lines (values mean ± 95% CI). Amiloride resulted in a reduction in wound closure at 50µM (-0.3425 ± [-0.5383 to -0.1466]) & 100µM (-0.4105 [ -0.5918 to -0.2292]) at 48hrs (mean reduction in area relative to vehicle [95% CI], 2-way ANOVA). Stage 3 OvCa tumours demonstrated a 4.996 ± 0.4247 (log2 ratio of Cq differences mean ±SEM) increase in α-ENaC in comparison to normal ovarian samples (unpaired t test, p<0.0001). Thus, Na+ channels result in a contribution to persistent permeability in OvCA. Na+ channel inhibition impedes proliferative & migratory capacity; two classical hallmarks of cancer. In addition, an upregulation of ENaC in metastatic OvCA suggests a promising future therapeutic target of biophysical alterations that occur in cancer using drugs that are already in clinical use.