PCK2-Mediated PQBP1 Lactylation Promotes Asthmatic Inflammation through PRMT5 Inhibition

  • Research (Wash D C). 2026 Jun 19:9:1321. doi: 10.34133/research.1321.
Qiaoyun Bai  1  2 ,  Ningpo Ding  1  2 ,  Rixin Feng  1  2 ,  Fengxiang Shang  1  2 ,  Zongqi Wang  1  2 ,  Liangchang Li  1  2 ,  Zhiguang Wang  1  3 ,  Yihua Piao  1  4 ,  Chongyang Wang  1  2 ,  Yilan Song  1  2  5 ,  Guanghai Yan  1  2  5
Affiliations
  • 1. Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, P.R. China.
  • 2. Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji 133002, P.R. China.
  • 3. Department of Respiratory Medicine, Affiliated Hospital of Yanbian University, Yanji 133000, P.R. China.
  • 4. Department of Critical Care Medicine, Affiliated Hospital of Yanbian University, Yanji 133000, P.R. China.
  • 5. Key Laboratory of Natural Medicines of Changbai Mountain, Ministry of Education, Yanbian University, Yanji 133002, P.R. China.
PMID: 42327952 DOI: 10.34133/research.1321
Abstract

Background: Asthma involves chronic inflammation linked to metabolic reprogramming, but how metabolites reshape Epigenetics through posttranslational modifications remains unclear. Methods: We used house dust Mite (HDM)-induced asthmatic mice with multiomics analyses (metabolomics, posttranslational modification-proteomics, and chromatin immunoprecipitation Sequencing) and validated findings through gene editing and adeno-associated virus interventions. Results: Asthmatic airways showed lactate-driven glutaminolysis, causing lactate/succinate accumulation. Phosphoenolpyruvate carboxykinase 2 (PCK2) succinylation at K100 enhanced stability by antagonizing ubiquitination, creating a lactate-generating feedback loop. Accumulated lactate triggered polyglutamine-binding protein 1 (PQBP1) lactylation at K223, enabling protein arginine methyltransferase 5 (PRMT5)/WD repeat domain 77 complex inhibition. This erased H4R3me2s repressive marks from proinflammatory gene promoters, particularly mitogen-activated protein kinase pathway genes, causing transcriptional derepression. Airway epithelium-specific Pqbp1 knockout reduced inflammation, goblet cell hyperplasia, and T helper 2 responses. Pck2-short hairpin RNA or oxamate treatment ameliorated asthmatic pathology. Conclusion: We identified a PCK2-lactate-PQBP1-PRMT5 axis linking metabolic reprogramming to epigenetic dysregulation in asthma. PCK2-K100 succinylation drives lactate accumulation, inducing PQBP1-K223 lactylation that inhibits PRMT5 and activates inflammatory genes, representing a therapeutic target for asthma.

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