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  3. Lactate-driven ATP6V1B2 lactylation triggers asthmatic inflammation by linking lysosomal dysfunction to mitochondrial ROS-dependent pyroptosis

Lactate-driven ATP6V1B2 lactylation triggers asthmatic inflammation by linking lysosomal dysfunction to mitochondrial ROS-dependent pyroptosis

  • Redox Biol. 2026 Mar:90:104059. doi: 10.1016/j.redox.2026.104059.
Qiaoyun Bai 1,  Ningpo Ding 1,  Rixin Feng 1,  Fengxiang Shang 1,  Zongqi Wang 1,  Liangchang Li 1,  Zhiguang Wang 2,  Yihua Piao 3,  Guangyu Jin 4,  Yilan Song 5,  Guanghai Yan 6
Affiliations

Affiliations

  • 1 Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji, 133002, PR China.
  • 2 Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, 133002, PR China; Department of Respiratory Medicine, Affiliated Hospital of Yanbian University, Yanji, 133000, PR China.
  • 3 Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, 133002, PR China; Department of Critical Care Medicine, Affiliated Hospital of Yanbian University, Yanji, 133000, PR China.
  • 4 Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, 133002, PR China; Department of Radiology, Affiliated Hospital of Yanbian University, No.1327, Juzi Street, Yanji, Jilin Province, 133000, PR China. Electronic address: [email protected].
  • 5 Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji, 133002, PR China; Key Laboratory of Natural Medicines of Changbai Mountain, Ministry of Education, Yanbian University, Yanji, 133002, PR China. Electronic address: [email protected].
  • 6 Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji, 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji, 133002, PR China; Key Laboratory of Natural Medicines of Changbai Mountain, Ministry of Education, Yanbian University, Yanji, 133002, PR China. Electronic address: [email protected].
PMID: 41637881 DOI: 10.1016/j.redox.2026.104059
Abstract

Immunometabolic reprogramming is increasingly recognized as a driver of asthma pathogenesis, yet the molecular mechanisms linking lactate accumulation to airway inflammation via protein lactylation (Kla) remain elusive. In this study, we integrated a house dust Mite (HDM)-induced asthma model with quantitative lactylomics to identify ATP6V1B2, a key V-ATPase subunit, as a core lactylation target. Combined molecular dynamics simulations and biochemical analyses revealed that intracellular l-lactate triggers lactylation at K108/K109. This modification restricts ATP6V1B2 conformational flexibility, leading to the disassembly of the V1-V0 complex and subsequent loss of Proton Pump activity. Crucially, the lactylation event was validated in primary human bronchial epithelial cells (HBEs), confirming that HDM and l-lactate stimulation induce ATP6V1B2 lactylation, thereby ensuring the clinical relevance of our findings. We demonstrate that this loss-of-function precipitates lysosomal alkalinization and membrane permeabilization (LMP). Crucially, LMP acts as a central node that bifurcates into two pathogenic cascades: it triggers a catastrophic mitochondrial ROS burst via Cathepsin B leakage. This oxidative burst functions as a pivotal redox signal that initiates a non-canonical Caspase-8/3/GSDME-dependent Pyroptosis pathway, distinct from intrinsic Apoptosis. In vivo, blocking ATP6V1B2 lactylation using an AAV-delivered lactylation-deficient (2 KR) mutant successfully severed this metabolic-inflammatory loop, significantly attenuating airway inflammation, Th2 cytokine release, and tissue Pyroptosis. These findings characterize a novel "l-lactate-ATP6V1B2-GSDME" axis, establishing ATP6V1B2 lactylation as a critical metabolic switch connecting lysosomal damage to inflammatory cell death, thereby identifying a potential therapeutic target for metabolic dysregulation in chronic asthma with severe pathology.

Keywords

ATP6V1B2; Asthma; Lactylation; Lysosomal dysfunction; Pyroptosis.

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