# Exceptionally selective voltage-sensor trapping of NaV1.5 channels by Mg-protoporphyrin impairs cancer cell migration

## TL;DR

A compound called Mg-protoporphyrin selectively inhibits a sodium channel linked to cancer cell migration, offering a potential new anti-cancer drug target.

## Contribution

Mg-protoporphyrin is identified as an exceptionally specific and potent inhibitor of the hNaV1.5 sodium channel in cancer cells.

## Key findings

- Mg-protoporphyrin inhibits hNaV1.5 with an IC50 of 1 nM and does not affect other sodium channel isoforms.
- Mg-protoporphyrin stabilizes the voltage sensor of hNaV1.5 in a deactivated state via residues E795 and N803.
- Mg-protoporphyrin suppresses cell migration in breast and colorectal cancer cell lines.

## Abstract

The human voltage-gated sodium channel hNaV1.5 is essential for cardiac excitability. Though underrecognized, NaV1.5 is also expressed in multiple cancers, promoting cell migration and malignancy. hNaV1.5 is a therapeutic target but limited pharmacological isoform specificity presents a risk of side effects via neuronal and skeletal muscle NaV channels. Here we identify Mg2+-protoporphyrin IX (MgPpIX), a Mg-containing tetrapyrrole and intermediate in chlorophyll biosynthesis, as a potent inhibitor of hNaV1.5 (IC50 of 1 nM). The activity profile of various metal protoporphyrins correlates with the electrostatic potential at the metal center of the compounds. MgPpIX is specific to hNaV1.5, as no inhibition of other hNaV isoforms (hNaV1.2, 1.4, 1.7, 1.8) was detected. A mutagenesis study and structural modeling reveals that MgPpIX stabilizes the domain-II voltage sensor in the deactivated conformation, with residues E795 and N803 being relevant determinants. MgPpIX also inhibits native NaV channels in breast cancer MDA-MB-231 and colorectal carcinoma SW-480 cell lines, and suppresses cell migration. MgPpIX is an exceptionally potent and specific inhibitor of hNaV1.5 and may serve as a lead compound in anti-cancer drug development.

The online version contains supplementary material available at 10.1038/s41598-026-37492-0.