A Pumilio-dependent post-transcriptional mechanism drives pulmonary hypertension via KCNK3 suppression

Pulmonary hypertension (PH) is a lethal vascular disorder characterized by obstructive remodelling of pulmonary arteries, driven predominantly by pathological phenotypes of pulmonary artery smooth muscle cells (PASMCs), including excessive proliferation, migration, and resistance to apoptosis. While the RNA-binding protein PUM2 and the potassium channel KCNK3 have been implicated in cardiovascular pathophysiology, their functional interplay in hypoxic pulmonary vascular remodelling remains undefined. Here, using rat models of PH (Sugen5416/hypoxia and monocrotaline), human PASMCs, and mechanistic assays, we identify a signalling axis in which hypoxia induces HIF1α-dependent transcriptional upregulation of PUM2. PUM2 in turn binds the 3'UTR of KCNK3 mRNA, destabilizing the transcript and reducing KCNK3 protein expression. Knockdown of PUM2 restored KCNK3 expression, promoted apoptosis, and suppressed proliferation and migration in PASMCs, whereas PUM2 overexpression exerted opposing effects. These phenotypic changes were reversed by concomitant KCNK3 knockdown, confirming KCNK3 as a critical downstream effector. In vivo, AAV9-mediated PUM2 knockdown ameliorated haemodynamic impairment, vascular remodelling, and right ventricular hypertrophy in PH rats, whereas PUM2 overexpression exacerbated disease progression. Notably, the related family member PUM1 exhibited similar hypoxia-induced upregulation and direct binding to KCNK3 mRNA, suggesting potential functional redundancy within the Pumilio family. Collectively, our results unveil a Pumilio-dependent post-transcriptional mechanism as a central driver of PASMC dysfunction in PH and nominate PUM2-and potentially other Pumilio family members-as promising therapeutic targets for mitigating hypoxic pulmonary vascular remodelling.