KLF6 in Pulmonary Hypertension: The Dual Role of Friend and Foe

Background: Pulmonary arterial hypertension (PAH) is a severe lung condition with unmet clinical needs, marked by endothelial damage, excessive repair, and arterial narrowing, though mechanisms remain unclear. Methods: This study investigates Kruppel-like transcription factor 6 (KLF6), known for its role in tissue injury response and cancer onset, in PAH through functional and expression analyses in human pulmonary artery endothelial cells (HPAECs) and human and rodent PAH lung tissues. Findings: KLF6 expression increased in early experimental PAH in response to hypoxia and inflammation, while the expression of endothelial homeostasis regulators KLF2 and KLF4, previously linked to PAH, decreased. KLF6 overexpression enhanced pulmonary endothelial survival and angiogenesis through broad transcriptomic remodelling, including changes in genes governing endothelial homeostasis and arterial identity (e.g., SOX17, ERG, BMPR2) and promoted human pulmonary artery smooth muscle cells (HPASMCs) proliferation, which was inhibited by bosentan and imatinib. KLF6 functional and transcriptomic responses differed from those of KLF2 and KLF4. Comparative analysis of RNA-seq PAH databases and spatial transcriptomic analysis of human idiopathic PAH (IPAH) tissues highlighted strong association of KLF6 with vascular remodelling, especially with the formation of angioproliferative (plexiform) lesions. High KLF6 expression was observed in IPAH vascular endothelium and IPAH blood-derived endothelial progenitor cells. Single nucleus RNA-seq in PAH associated with Alveolar Capillary Dysplasia confirmed disease-related elevated KLF6 expression in arterial endothelial cells. Interpretation: Accumulation and reorganization of KLF6+ endothelial cells characterize human PAH. KLF6 drives endothelial repair and an apoptosis-resistant, angioproliferative endothelial phenotype. Targeting KLF6 could be a novel therapeutic approach for PAH.