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Transl. Med."],"published-print":{"date-parts":[[2026,10,21]]},"abstract":"<jats:p>\n                    ZIP12, a membrane-bound zinc importer, is up-regulated in the remodeled pulmonary arterioles of patients with pulmonary arterial hypertension (PAH). Genetic deletion of its encoding gene,\n                    <jats:italic toggle=\"yes\">Slc39a12<\/jats:italic>\n                    , ameliorates the disease in rodent models. Here, we show that ZIP12 overexpression in human pulmonary artery smooth muscle cells (PASMCs) increased intracellular labile Zn\n                    <jats:sup>2+<\/jats:sup>\n                    and promoted proliferation. ZIP12 siRNA knockdown attenuated pulmonary hypertension in rodent models. We developed a humanized anti-ZIP12 monoclonal antibody, APL-9796, that normalized intracellular Zn\n                    <jats:sup>2+<\/jats:sup>\n                    concentration, suppressed proliferation in fibroblasts derived from patients with PAH and PDGF-stimulated PASMCs, and reduced PDGF-induced cytoskeletal remodeling in PASMCs and contractility in PASMCs and engineered pulmonary artery tissues. APL-9796 showed dose-dependent efficacy in humanized\n                    <jats:italic toggle=\"yes\">Slc39a12<\/jats:italic>\n                    rats, improving cardiopulmonary parameters after induction of pulmonary hypertension and was well tolerated in phase 1 clinical studies. Transcriptomic profiling revealed modulation of several molecular pathways, including those involving AMPK, PPAR, and PI3K-Akt. ZIP12-driven labile Zn\n                    <jats:sup>2+<\/jats:sup>\n                    signaling underpins the pathogenesis of PAH. Targeting ZIP12 with APL-9796 offers a promising therapeutic strategy.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.aee0680","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T17:58:57Z","timestamp":1792605537000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Targeting ZIP12-mediated Zn\n                    <sup>2+<\/sup>\n                    signaling as a treatment for pulmonary hypertension"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1177-5568","authenticated-orcid":true,"given":"Lan","family":"Zhao","sequence":"first","affiliation":[{"name":"National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7664-6103","authenticated-orcid":true,"given":"Stephanie","family":"Hopley","sequence":"additional","affiliation":[{"name":"Apollo Therapeutics Limited, Cambridge, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8705-5674","authenticated-orcid":true,"given":"Chien-Nien","family":"Chen","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iyobel","family":"Kibreab","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, 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UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2994-2387","authenticated-orcid":true,"given":"Lin","family":"Zhao","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9975-3795","authenticated-orcid":true,"given":"Adam","family":"Fellows","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0842-2526","authenticated-orcid":true,"given":"Daria S.","family":"Kostyunina","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9340-882X","authenticated-orcid":true,"given":"Eduardo","family":"Oliver","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6514-0376","authenticated-orcid":true,"given":"Shu","family":"Ning","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, 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