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The precise functional roles and regulatory networks of cystathionine \u03b3-lyase (CSE), a primary hydrogen sulfide (H\u2082S)-producing enzyme, in thyroid cancer metastasis were then investigated in cell and mice models. Finally, these findings were further validated in a cohort of clinical pathological samples.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified that CSE is aberrantly silenced in advanced thyroid cancer. Mechanistically, BRAF V600E-driven MAPK activation upregulates\n                      <jats:italic>miR-31-5p<\/jats:italic>\n                      , which directly targets the\n                      <jats:italic>CSE<\/jats:italic>\n                      3\u2019UTR to inhibit its translation. The consequent H\u2082S deficiency disrupts intracellular metallo-homeostasis, triggering intracellular zinc accumulation that stabilizes Zeb1, MMP-2, thereby orchestrating the epithelial-mesenchymal transition (EMT). Critically, the metastatic potential of thyroid cancer cells relies strictly on CSE enzymatic activity. Pharmacological reconstitution of the H\u2082S pool using exogenous donors effectively bypasses CSE enzymatic deficiency, eliminates excess zinc, and reactivates metastasis-suppressive signaling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These findings uncover a novel\n                      <jats:italic>miR-31-5p<\/jats:italic>\n                      \/CSE\/H\u2082S\/Zinc axis that fuels BRAF-driven progression. These findings provide a compelling mechanistic rationale for utilizing H\u2082S-based interventions as a potential therapeutic strategy against BRAF-driven thyroid cancer metastasis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-026-03752-0","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T02:56:12Z","timestamp":1781060172000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Loss of CSE couples with BRAF V600E to fuel thyroid cancer metastatic progression through zinc-dependent activation of the EMT machinery"],"prefix":"10.1186","volume":"45","author":[{"given":"Shichen","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huixin","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxun","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongfu","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajie","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Botao","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gangming","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobo","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donghui","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiandong","family":"Bao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1740-8833","authenticated-orcid":false,"given":"Li","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"issue":"3","key":"3752_CR1","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1016\/j.cell.2014.09.050","volume":"159","author":"Cancer Genome Atlas Research","year":"2014","unstructured":"Cancer Genome Atlas Research. 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All procedures were approved by the Institutional Review Board (or Ethics Committee) of Jiangsu Institute of Nuclear Medicine (protocol number: YL202120. 1st, January 2021). All animal procedures were performed in strict compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and were approved by the Institutional Review Board of Jiangsu Institute of Nuclear Medicine.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Consent was obtained from each patient.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"178"}}