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Though underrecognized, Na\n                    <jats:sub>V<\/jats:sub>\n                    1.5 is also expressed in multiple cancers, promoting cell migration and malignancy. hNa\n                    <jats:sub>V<\/jats:sub>\n                    1.5 is a therapeutic target but limited pharmacological isoform specificity presents a risk of side effects via neuronal and skeletal muscle Na\n                    <jats:sub>V<\/jats:sub>\n                    channels. Here we identify Mg\n                    <jats:sup>2+<\/jats:sup>\n                    -protoporphyrin IX (MgPpIX), a Mg-containing tetrapyrrole and intermediate in chlorophyll biosynthesis, as a potent inhibitor of hNa\n                    <jats:sub>V<\/jats:sub>\n                    1.5 (\n                    <jats:italic>IC<\/jats:italic>\n                    <jats:sub>50<\/jats:sub>\n                    of 1\u00a0nM). The activity profile of various metal protoporphyrins correlates with the electrostatic potential at the metal center of the compounds. MgPpIX is specific to hNa\n                    <jats:sub>V<\/jats:sub>\n                    1.5, as no inhibition of other hNa\n                    <jats:sub>V<\/jats:sub>\n                    isoforms (hNa\n                    <jats:sub>V<\/jats:sub>\n                    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\n                    <jats:sub>V<\/jats:sub>\n                    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 hNa\n                    <jats:sub>V<\/jats:sub>\n                    1.5 and may serve as a lead compound in anti-cancer drug development.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-37492-0","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T05:15:05Z","timestamp":1769663705000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exceptionally selective voltage-sensor trapping of NaV1.5 channels by Mg-protoporphyrin impairs cancer cell migration"],"prefix":"10.1038","volume":"16","author":[{"given":"Mahdi","family":"Jamili","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marwa","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alisa","family":"Bernert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johann","family":"R\u00f6\u00dfler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guido","family":"Gessner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roland","family":"Sch\u00f6nherr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshinori","family":"Hoshi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4144-0251","authenticated-orcid":false,"given":"Stefan H.","family":"Heinemann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,1,29]]},"reference":[{"key":"37492_CR1","doi-asserted-by":"publisher","first-page":"124","DOI":"10.3389\/fphar.2012.00124","volume":"3","author":"E Savio-Galimberti","year":"2012","unstructured":"Savio-Galimberti, E., Gollob, M. 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