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Adv."],"published-print":{"date-parts":[[2026,7,17]]},"abstract":"<jats:p>\n                    Pancreatic ductal adenocarcinoma (PDA) is an aggressive cancer that frequently presents with disseminated disease. The PDA metastatic microenvironment imposes distinct metabolic stressors, potentially generating context-dependent vulnerabilities. Therefore, we employed CRISPR-based genetic screening in a model of PDA liver metastasis to identify novel and possibly targetable liabilities. Remarkably, ferritin heavy chain (FTH1) emerged as the most prominent liver-specific dependency \u2013 loss of FTH1 suppressed tumor growth specifically in the liver microenvironment. FTH1 deletion and subsequent disruption of iron handling triggers mitochondrial dysfunction and ionic imbalance, including cytosolic calcium overload. These perturbations result in the activation of a transcriptional program that triggers anti-tumor immunity mediated by immunostimulatory cytokine IL36G. Mechanistically, FTH1 deletion and subsequent ionic imbalance causes decreased protein levels of the tumor suppressor\n                    <jats:italic toggle=\"yes\">Stk11<\/jats:italic>\n                    (LKB1) which we propose to be mediated by an RNA G-quadruplex located in the 5\u2032-UTR of LKB1. The loss of LKB1 protein levels alters signaling cascades resulting in reduced SIK signaling and inhibition of nonsense mediated decay, ultimately leading to\n                    <jats:italic toggle=\"yes\">Il36g<\/jats:italic>\n                    mRNA stabilization. Taken together, this work elucidates novel ionic disruptions that regulate the translation of LKB1 through a previously undescribed quadruplex in the 5\u2032UTR, altering signaling axes that can be targeted to generate an anti-tumor immune response in PDA.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adz8681","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T17:58:48Z","timestamp":1784311128000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Iron overload suppresses LKB1 and induces IL36G anti-tumor immunity in PDAC metastasis"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8800-7124","authenticated-orcid":true,"given":"Douglas E.","family":"Biancur","sequence":"first","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine; New York, NY 10016 USA."},{"name":"Perlmutter Cancer Center, New York University Grossman School of Medicine; New York, NY 10016, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harsha","family":"Venkatesh","sequence":"additional","affiliation":[{"name":"Department of Chemistry, New York University, New York, NY 10003, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6147-7716","authenticated-orcid":true,"given":"Amy","family":"Crawford","sequence":"additional","affiliation":[{"name":"Department of Chemistry, New York University, New York, NY 10003, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7850-5418","authenticated-orcid":true,"given":"Yealeen","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine; New York, NY 10016 USA."},{"name":"Perlmutter Cancer Center, New York University Grossman School of Medicine; New York, NY 10016, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7869-4362","authenticated-orcid":true,"given":"Albert S.W.","family":"Sohn","sequence":"additional","affiliation":[{"name":"Perlmutter Cancer Center, New York University Grossman School of Medicine; New York, NY 10016, USA."},{"name":"Department of Radiation Oncology. 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