Exploring Neonatal NaV1.5 Voltage-Gated Sodium Channel as a Therapeutic Target in Cancer

Abstract

Voltage-gated sodium channels (VGSCs) play pivotal roles in cancer progression and have emerged as promising therapeutic targets and biomarkers. VGSCs comprise multiple subtypes with distinct tissue distributions, influencing tumour characteristics in different ways. Among these, the tetrodotoxin-sensitive α-subunits and the β1 subunit, commonly found in breast cancer, have been implicated in metastasis and tumour aggressiveness. The NaV1.5 channel and its neonatal variant (nNaV1.5) are overexpressed in aggressive cancers such as breast, prostate, colorectal, and lung cancers, thereby enhancing their invasive capacity. nNaV1.5 is particularly significant due to its tumour-specific expression and strong association with poor prognosis, especially in breast cancer, where it regulates cell proliferation, invasion, and tumour microenvironment remodelling. This review highlights nNaV1.5 as a critical ion channel that drives metastasis through ion regulation, extracellular acidification, and cytoskeletal remodelling. We further evaluate current therapeutic strategies, including siRNA, monoclonal antibodies, and small-molecule inhibitors, while addressing translational challenges such as tumour heterogeneity, drug delivery limitations, and off-target cardiotoxicity due to its similarity with the adult isoform. In addition, we explore the potential of nNaV1.5 as a biomarker subject to epigenetic regulations by factors including RE1-silencing transcription factor (REST) and histone deacetylase 2 (HDAC2), which may facilitate patient stratification and treatment optimization. By integrating mechanistic insights, therapeutic opportunities, and translational challenges, this review goes beyond descriptive summaries to provide a framework for advancing nNaV1.5 research from preclinical studies toward clinical application in cancer therapy.