Long noncoding RNA FGD5-AS1-encoded micropeptides improve right heart functions of pulmonary arterial hypertension through restricting the synthesis of hyaluronic acid

Pulmonary arterial hypertension (PAH) is marked by elevated vascular resistance, right ventricular (RV) failure, and poor clinical outcomes. Current therapies primarily target pulmonary vascular hemodynamics, necessitating novel strategies to address RV remodeling. In this study, we investigated the role of lncRNA FGD5-AS1 and its micropeptides in PAH and RV remodeling, focusing on their effects on hyaluronic acid (HA) synthesis and extracellular matrix organization. FGD5-AS1 expression was significantly reduced in peripheral blood mononuclear cells of PAH patients and inversely correlated with HA levels and disease severity. Functional studies using FGD5-AS1 knockout (KO) in the AC16 human cardiomyocyte cell line led to upregulation of HAS2, increased HA production and activation of TLR4, contributing to pro-fibrotic and pro-hypertrophic responses. In a monocrotaline-induced PAH rat model, overexpression of FGD5-AS1 encoded micropeptide Pep1 reduced HA synthesis, suppressed heart failure biomarkers (NPPA, NPPB), and improved cardiac function, while Pep2 showed limited benefits. These findings demonstrate that FGD5-AS1 exerts protective effects in PAH by modulating HA synthesis through HAS2 regulation. The micropeptides, particularly Pep1, offer promising therapeutic potential for improving RV function and remodeling in PAH. This study highlights FGD5-AS1 and its derived micropeptides as novel therapeutic targets for PAH, providing new strategies to address RV dysfunction in this debilitating disease.