STK39 is associated with endothelial dysfunction and inflammatory activation under hypoxic conditions in moyamoya disease

Moyamoya disease (MMD) is a cerebrovascular disease whose mechanism relatively unknown and can cause vascular occlusion and hyperplasia. This study aimed to explore molecular heterogeneity associated with the expression of acetylation-related genes in MMD and to identify candidate genes potentially involved in vascular endothelial dysfunction.

Public MMD transcriptomic datasets were analyzed using a predefined acetylation-regulatory gene set to identify expression clusters and prioritize cluster-associated candidate genes. Functional enrichment, immune-infiltration, and predicted miRNA-mRNA network analyses were performed to characterize candidate-associated molecular features. Serum STK39 and MTMR12 concentrations were assessed by ELISA in a preliminary study of three patients with MMD and three healthy controls. STK39 was further investigated in human brain microvascular endothelial cells (HBMECs) using siRNA-mediated knockdown under normoxic and hypoxic conditions, with Trichostatin A (TSA) treatment included as an exploratory pharmacological intervention.

Consensus clustering was used to classify MMD into two subtypes, and five key subtype-related genes were identified: STK39, NEO1, PKNOX1, GOLT1B, and MTMR12. In the validation cohort, serum STK39 and MTMR12 levels were significantly decreased in patients with MMD. In vitro, STK39 knockdown promoted HBMEC migration, inhibited proliferation, and increased the expression of HIF-1α, p-STAT3, cleaved Caspase-3, IL-6, CCL2, and VCAM-1 under hypoxic conditions, whereas TSA treatment partially reversed these changes.

Acetylation-related genes are closely associated with the molecular heterogeneity of MMD. Among them, STK39 appears to participate in hypoxia-related endothelial dysfunction and inflammatory activation. These findings provide new insight into the role of acetylation-related pathways in MMD pathogenesis and suggest potential targets for future mechanistic studies.