ZIP12-driven labile Zn2+ signaling underpins the pathogenesis of PAH, and targeting ZIP12 with the humanized monoclonal antibody APL-9796 offers a promising therapeutic strategy.
ZIP12 is up-regulated in the remodeled pulmonary arterioles of patients with pulmonary arterial hypertension, and genetic deletion of Slc39a12 ameliorates disease in rodent models.
ZIP12 overexpression in human pulmonary artery smooth muscle cells increased intracellular labile Zn2+ and promoted proliferation.
siRNA knockdown of ZIP12 attenuated pulmonary hypertension in rodent models.
The humanized anti-ZIP12 monoclonal antibody APL-9796 normalized intracellular Zn2+ concentration and suppressed proliferation in PAH patient-derived fibroblasts and PDGF-stimulated PASMCs.
APL-9796 reduced PDGF-induced cytoskeletal remodeling in PASMCs and reduced 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.
APL-9796 was well tolerated in phase 1 clinical studies.
Transcriptomic profiling showed that APL-9796 modulates several molecular pathways, including AMPK, PPAR, and PI3K-Akt.
Pulmonary arterial hypertension (PAH) is a serious disease in which the small blood vessels in the lungs thicken and narrow, straining the heart. Earlier work found that a protein called ZIP12, which brings zinc into cells, is increased in the damaged lung vessels of patients. This study tested whether blocking ZIP12 could help. The researchers found that boosting ZIP12 in human lung vessel muscle cells raised free zinc inside the cells and made them multiply more. Reducing ZIP12 with siRNA eased pulmonary hypertension in rodents. They then developed an antibody drug, APL-9796, that blocks ZIP12. In lab experiments it brought zinc levels back to normal, slowed cell growth (including in cells from PAH patients), and reduced cell structural changes and contraction in cells and engineered lung artery tissue. In specially engineered rats carrying the human version of the gene, it improved heart and lung measures in a dose-dependent way. It was also well tolerated in early phase 1 human safety studies, and gene activity analyses suggested it affects several cell signaling pathways (AMPK, PPAR, PI3K-Akt). This research suggests that zinc signaling through ZIP12 plays a central role in PAH and that blocking it may be a promising treatment approach. The evidence so far comes from cells, engineered tissues, animals, and early safety studies in people, so whether it helps patients with PAH has not yet been shown.
Zhao L, Hopley S, Chen C, Kibreab I, Xie C, Baxan N, et al.. (2026). Targeting ZIP12-mediated Zn2+ signaling as a treatment for pulmonary hypertension.. Science translational medicine. https://doi.org/10.1126/scitranslmed.aee0680