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.

Introduction: Aquilaria malaccensis, also known as “Pokok Karas” in Malaysia, is widely used in Southeast Asian countries for the treatment of joint pain, diarrhoea and inflammatory diseases, and has shown beneficial effects as an anticancer agent. The aim of this study was to investigate the effect of ethanol leaf extracts of A. malaccensis on MCF-7 cells. Methods: MTT-based cytotoxic and antiproliferative assay was used to determine the outcome of ethanolic extract toward MCF-7 cells. The mode of cell death was determined by the AO/PI double staining assay and the depolarisation of the mitochondria membrane potential. Results: IC50 value of the extract against MCF-7 cells treated for 72 hours was 4.1 ± 2.08 µg/mL, while the IC50 value for doxorubicin was 2.92 ± 0.12 µg/mL. The extract showed a lower cytotoxic effect against the NIH/3T3 cells and inhibited the growth of MCF-7 cells in a dose dependent manner. AO/PI double stain showed that the ethanolic extract of A. malaccensis leaves induced MCF-7 cells into apoptotic cell death. The present study showed that the ethanolic extract of A. malaccensis induced apoptosis through mitochondrial pathway as indicated by its ability to take up JC-1. Conclusion: The study found that ethanolic extract obtained from A. malaccensis leaves is cytotoxic on MCF-7 cells, resulting to apoptotic cell death of the cells.