Circ_0068481 promotes pulmonary arterial smooth muscle cell remodeling via PTEN degradation and PI3K/AKT signaling activation.

Pulmonary arterial hypertension (PAH) is a progressive vascular disease characterized by pulmonary vascular remodeling and elevated pulmonary artery pressure. Although circ_0068481, a circular RNA, has been implicated in PAH, its functional roles and underlying mechanisms remain unclear. This study aimed to investigate the role of circ_0068481 in PAH-associated cellular dysfunction and to explore its potential molecular mechanism. Expression of circ_0068481 was measured in serum samples from PAH patients and in human pulmonary artery smooth muscle cells (hPASMCs) under normoxic and hypoxic conditions. Functional effects of circ_0068481 knockdown or overexpression were assessed using Cell Counting Kit-8 (CCK-8), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and scratch assays. Western blot evaluated apoptosis-, phenotype-, and pathway-related proteins. RNA immunoprecipitation (RIP) and co-immunoprecipitation assays were used to examine the association between circ_0068481 and phosphatase and tensin homolog (PTEN) and its effect on PTEN ubiquitination. Circ_0068481 was significantly upregulated in the serum of PAH patients and in hypoxia-treated hPASMCs. In vitro, circ_0068481 overexpression promoted hPASMC proliferation, migration, and phenotypic switching while inhibiting apoptosis. Mechanistically, circ_0068481 was associated with reduced PTEN protein abundance and enhanced PTEN ubiquitination, accompanied by activation of the PI3K/AKT signaling pathway. The combined knockdown of circ_0068481 and PTEN partially reversed these cellular effects. These findings identify circ_0068481 as a regulator of PTEN stability and PI3K/AKT signaling in hPASMCs under hypoxic conditions and suggest a circRNA-mediated post-translational regulatory mechanism that may be relevant to pulmonary vascular remodeling in PAH.