ALDOB K87 lactylation drives mitochondrial fission and metabolic reprogramming in pulmonary hypertensionDownload PDF Download PDF ArticleOpen accessPublished: 27 March 2026Liu Yi1,2,3,Wenming He3,Changqing He1,Xianbao Shi4,Xiaodong Deng2,Jinyu Chang1,Jie Ni2,Li Liu5 &…Lina Shan ORCID: orcid.org/0000-0002-5392-52991 Communications Biology , Article number: (2026) Cite this article We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.SubjectsPost-translational modificationsSumoylationTranscriptional regulatory elementsAbstractPulmonary hypertension (PH) is a life-threatening disorder characterized by progressive pulmonary vascular remodeling, occlusive arteriopathy, and right ventricular failure. However, the molecular mechanisms underlying these pathological hallmarks remain elusive. This study aimed to introduce aldolase B (ALDOB)-K87 lactylation as a critical regulator of mitochondrial fission and metabolic reprogramming in PH pathogenesis. Integrated lactylomic profiling in hypoxic human pulmonary artery smooth muscle cells (PASMCs) and validation in rodent PH models revealed that hypoxia-induced ALDOB-K87 lactylation amplified glycolytic flux, fostering lactate accumulation and self-reinforcing lactylation. Mechanistically, ALDOB lactylation recruited dynamin-related protein 1 (DRP1) to mitochondria via sentrin/SUMO-specific peptidase 3–mediated deSUMOylation of DRP1. This facilitated mitochondrial fragmentation, exacerbating PASMC proliferation, migration, and phenotypic switching. Sirtuin 1 serves as a delactylase for ALDOB, and its downregulation in PH sustains lactylation-driven pathology. Genetic or pharmacological suppression of ALDOB lactylation attenuates mitochondrial fission and PH progression in vivo, whereas lactylation-mimetic mutants exacerbate disease phenotypes. This study unveiled a lactate–ALDOB–DRP1 axis that bridged metabolic rewiring with mitochondrial dynamics, offering novel therapeutic targets for PH.Data availabilityAll raw data for the charts are provided in Supplementary Data 1. Lactylation proteomics data has been provided in Supplementary Data 2. Unprocessed scans of gels/blots can be found in the Supplementary Information file. All other data are available from the corresponding author on reasonable request.ReferencesMocumbi, A. et al. Pulmonary hypertension. Nat. Rev. Dis. Prim. 10, 1 (2024).Google Scholar Zeder, K., Siew, E. D., Kovacs, G., Brittain, E. L. & Maron, B. A. Pulmonary hypertension and chronic kidney disease: Prevalence, pathophysiology and outcomes. Nat. Rev. Nephrol. 20, 742–754 (2024).Google Scholar Wu, J. et al. 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We appreciate the support of the aforementioned funds and all the reviewers and editorial teams who have contributed to this article.Author informationAuthors and AffiliationsDepartment of Respiratory Disease, The First Affiliated Hospital, Jinzhou Medical University, Jinzhou, ChinaLiu Yi, Changqing He, Jinyu Chang & Lina ShanDepartment of Critical Care Medicine, Panzhihua Central Hospital, Panzhihua, ChinaLiu Yi, Xiaodong Deng & Jie NiDepartment of Cardiovascular Disease, The First Affiliated Hospital, Ningbo University, Ningbo, ChinaLiu Yi & Wenming HeDepartment of Pharmacy, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, ChinaXianbao ShiDepartment of Neurology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, ChinaLi LiuAuthorsLiu YiView author publicationsSearch author on:PubMed Google ScholarWenming HeView author publicationsSearch author on:PubMed Google ScholarChangqing HeView author publicationsSearch author on:PubMed Google ScholarXianbao ShiView author publicationsSearch author on:PubMed Google ScholarXiaodong DengView author publicationsSearch author on:PubMed Google ScholarJinyu ChangView author publicationsSearch author on:PubMed Google ScholarJie NiView author publicationsSearch author on:PubMed Google ScholarLi LiuView author publicationsSearch author on:PubMed Google ScholarLina ShanView author publicationsSearch author on:PubMed Google ScholarContributionsAll authors significantly contributed to the study, including its conception, design, execution, data acquisition, analysis, and interpretation. They were also involved in drafting, revising, or critically reviewing the manuscript; approved the final version for publication; agreed on the journal for manuscript submission; and accepted accountability for all aspects of the study. Y.L. designed the study, conducted the experiments, interpreted the results, and wrote the manuscript. X.D. and X.S. conducted the experiments and interpreted the results. C.H., J.C., and W.H. conducted the experiments. N.J. drew icons for statistical analysis. L.L. provided financial support. L.S. designed the study and revised the manuscript. All authors read and approved the final version of the manuscript.Corresponding authorCorrespondence to Lina Shan.Ethics declarationsCompeting interestsThe authors declare no competing interests.Consent for publicationAll authors consent to the publication of this manuscript.Peer reviewPeer review informationCommunications Biology thanks Swati Dabral and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Christina Karlsson Rosenthal. 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