@article{Zhao:2026:10.1126/scitranslmed.aee0680,
author = {Zhao, L and Hopley, S and Chen, C-N and Kibreab, I and Xie, C and Baxan, N and Ashek, A and Zhao, L and Fellows, A and Kostyunina, DS and Oliver, E and Wang, L and Ning, S and Rutter, G and Gorelik, J and Gurrell, R and Butt, R and Hamblin, P and Wilkins, MR},
doi = {10.1126/scitranslmed.aee0680},
journal = {Sci Transl Med},
title = {Targeting ZIP12-mediated Zn2+ signaling as a treatment for pulmonary hypertension.},
url = {http://dx.doi.org/10.1126/scitranslmed.aee0680},
volume = {18},
year = {2026}
}

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TY  - JOUR
AB  - 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, Slc39a12, ameliorates the disease in rodent models. Here, we show that ZIP12 overexpression in human pulmonary artery smooth muscle cells (PASMCs) increased intracellular labile Zn2+ 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 Zn2+ 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 Slc39a12 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 Zn2+ signaling underpins the pathogenesis of PAH. Targeting ZIP12 with APL-9796 offers a promising therapeutic strategy.
AU  - Zhao,L
AU  - Hopley,S
AU  - Chen,C-N
AU  - Kibreab,I
AU  - Xie,C
AU  - Baxan,N
AU  - Ashek,A
AU  - Zhao,L
AU  - Fellows,A
AU  - Kostyunina,DS
AU  - Oliver,E
AU  - Wang,L
AU  - Ning,S
AU  - Rutter,G
AU  - Gorelik,J
AU  - Gurrell,R
AU  - Butt,R
AU  - Hamblin,P
AU  - Wilkins,MR
DO  - 10.1126/scitranslmed.aee0680
PY  - 2026///
TI  - Targeting ZIP12-mediated Zn2+ signaling as a treatment for pulmonary hypertension.
T2  - Sci Transl Med
UR  - http://dx.doi.org/10.1126/scitranslmed.aee0680
UR  - https://www.ncbi.nlm.nih.gov/pubmed/42905856
VL  - 18
ER  - 

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