{"doi":"10.1101/2025.07.28.667138","title":"Voltage-sensor trapping of cardiac Na <sup>+</sup> channels by Mg-protoporphyrin impairs cancer cell migration","abstract":"Abstract The human voltage-gated sodium channel hNa V 1.5 is essential for cardiac excitability. Though underrecognized, Na V 1.5 is also expressed in multiple cancers, promoting cell migration and malignancy. hNa V 1.5 is a therapeutic target but limited isoform specificity presents a risk of side effects via neuronal and skeletal muscle Na V channels. Here we identify Mg 2+ -protoporphyrin IX (MgPpIX), a Mg-containing tetrapyrrole and intermediate in chlorophyll biosynthesis, as inhibitor of hNa V 1.5 (IC 50 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 hNa V 1.5, as no inhibition of other hNa V isoforms (hNa V 1.2, 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 Na V channels in breast cancer MDA-MB-231 and colorectal carcinoma SW480 cell lines, and suppresses cell migration. MgPpIX is an exceptionally potent and specific inhibitor of hNa V 1.5 and may serve as a lead compound in anti-cancer drug development.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":571089,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9646,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":2138,"name":"Marwa Ahmed","orcid":"0009-0005-2732-4923","position":1,"is_corresponding":false},{"id":427319,"name":"Alisa Bernert","orcid":null,"position":2,"is_corresponding":false},{"id":1477286,"name":"Johann Rossler","orcid":null,"position":3,"is_corresponding":false},{"id":926181,"name":"Guido Geßner","orcid":null,"position":4,"is_corresponding":false},{"id":427321,"name":"Roland Schönherr","orcid":null,"position":5,"is_corresponding":false},{"id":426214,"name":"Toshinori Hoshi","orcid":"0000-0002-0702-1918","position":6,"is_corresponding":false},{"id":426215,"name":"Stefan H. Heinemann","orcid":"0000-0002-4144-0251","position":7,"is_corresponding":false},{"id":930484,"name":"Mahdi Jamili","orcid":null,"position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T02:57:15.755535Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}