Int J Biol Macromol. 2025 Dec 26:149857. doi: 10.1016/j.ijbiomac.2025.149857. Online ahead of print.
ABSTRACT
OBJECTIVE: This study aimed to investigate the role of N-myc downstream regulated gene 1 (NDRG1) in regulating hypoxia-inducible factor (HIF)1α stability, metabolic reprogramming, and pulmonary vascular remodeling under hypoxic conditions in pulmonary hypertension (PH) to elucidate their interaction.
APPROACH AND RESULTS: Notably, in vitro cell cultures and in vivo mouse models revealed that acute hypoxia increased NDRG1 stability through the mechanistic target of rapamycin complex 2-dependent phosphorylation. In contrast, chronic hypoxia enhanced NDRG1 transcription through the binding of HIF1α to its promoter region. NDRG1 interaction inhibited the proline hydroxylation and proteasomal degradation of HIF1α, which, in turn, stabilized HIF1α. This stabilization promoted metabolic reprogramming and proliferation of pulmonary artery endothelial cells. Furthermore, disrupting the NDRG1-HIF1α axis, either through genetic knockout or Voglibose-mediated pharmacological inhibition, reduced vascular remodeling and right ventricular hypertrophy, indicating attenuation of PH progression.
CONCLUSION: Overall, the findings of this study identified a novel feed-forward NDRG1-HIF1α regulatory circuit in PH-related hypoxic signaling. The preclinical evidence suggests the therapeutic potential of the proposed pathway in PH management, with Voglibose emerging as a candidate for further drug development.
PMID:41456779 | DOI:10.1016/j.ijbiomac.2025.149857