ROC-325 Attenuates Hypoxia-Induced Pulmonary Hypertension Through Dual Inhibition of Autophagy and Hypoxia-Inducible Factor 2α Signaling

Abstract

The activation of autophagy in endothelial cells is a key mechanism underlying vascular remodeling, leading to the development and progression of pulmonary hypertension (PH). In our previous studies, we developed ROC-325, a novel lysosomal autophagy inhibitor, and demonstrated its potent therapeutic effects in severe pulmonary arterial hypertension (PAH). However, its role in chronic hypoxia-induced PH (HPH) remains unknown. Here, we observed increased LC3B-II/I and decreased p62/SQSTM1 in lung tissues of hypoxic mice, indicative of autophagy activation. ROC-325 treatment suppressed this activation by inhibiting LC3B-II accumulation and restoring p62 levels. ROC-325 significantly reduced right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), and pulmonary artery medial thickening and muscularization, indicating a significantly protective effect against HPH. Endothelial hypoxia-inducible factor 2α (HIF-2α) upregulation, resulting from prolyl hydroxylase domain protein 2 (PHD2) deficiency, was implicated in autophagy activation. Endothelial conditional PHD2 knockout mice, a spontaneous PH model, exhibited elevated LC3B-II/I and HIF-2α levels, both of which were reduced by ROC-325, leading to significant PH attenuation. In vitro, ROC-325 inhibited the proliferation of pulmonary microvascular endothelial cells derived from PHD2-deficient mice and enhanced HIF-2α degradation in human pulmonary artery endothelial cells. These findings, in summary, identify ROC-325 as a promising therapeutic agent for hypoxia-induced PH by modulating both autophagy and endothelial HIF-2α signaling.

Keywords

autophagy / autophagy inhibitor ROC-325 / endothelial cells / HIF-2α / hypoxia / pulmonary hypertension

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2026 The Author(s). MedComm – Future Medicine published by John Wiley & Sons Australia, Ltd on behalf of Sichuan International Medical Exchange & Promotion Association (SCIMEA).