Abstract
Pulmonary arterial hypertension (PAH) is a life-threatening metabolic disorder. Nuclear receptors REV-ERBα and REV-ERBβ are established regulators of circadian rhythm and metabolic homeostasis, however their roles in PAH remain unclear. Using Rev-erbα+/-, VSMC-specific Rev-erbα-/-, and Rev-erbβ-/- mice (only male mice were used in the study), along with pharmacological activation and AAV-mediated overexpression, we found that Rev-erbα deficiency, particularly in vascular smooth muscle cells (VSMCs), exacerbates Su5416+hypoxia (SuHx)-induced PAH, whereas REV-ERBα activation or overexpression alleviates disease. In contrast, Rev-erbβ loss does not affect PAH. Notably, late-stage administration of REV-ERBα agonist significantly improves established PAH. Mechanistically, REV-ERBα directly represses Bnip3 transcription, thereby inhibiting BNIP3-driven mitophagy and improving mitochondrial function in hypoxic pulmonary artery smooth muscle cells (PASMCs). Bnip3 knockdown phenocopies REV-ERBα activation, while Bnip3 overexpression abrogates REV-ERBα’s anti-proliferative effects and accelerates PAH. Collectively, REV-ERBα protects against PAH by inhibiting BNIP3-driven mitophagy and preserving mitochondrial homeostasis in PASMCs. Targeting the REV-ERBα/BNIP3 axis holds promise as a circadian-based therapeutic strategy for PAH.
Data availability
All data supporting the findings of this study are available within the paper and its Supplementary Information. The source data underlying all main and Supplementary figures. are provided as a publicly available Source Data file. Source data are provided with this paper.
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Acknowledgements
This work was supported by Noncommunicable Chronic Diseases-National Science and Technology Major Project (grant number: 2024ZD0528200 to L.C.) and National Natural Science Foundation of China (grant number: 32571348, 32071157 to L.C.).
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Conceptualization: L.Q., G.Y., L.C. Methodology: L.Q., T.L., J.Z., M.L., H.W., W.L., C.M., S.L., B.R., Q.W., F.F., H.X., F.Z., Y.G., X.Z. Investigation: L.Q., T.L., J.Z., M.L. Visualization: L.Q., T.L., J.Z., M.L., W.L. Supervision: G.Y., L.C. Writing—original draft: L.Q. Writing—review and editing: G.Y., L.C.
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Qiu, L., Lu, T., Zhang, J. et al. Targeting REV-ERBα/BNIP3 axis attenuates pulmonary arterial hypertension by repressing mitophagy in mice. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71189-2
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DOI: https://doi.org/10.1038/s41467-026-71189-2
