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

Summary

Using lactylomics in an HDM-asthma model and human bronchial epithelial cells, the authors identify ATP6V1B2 lactylation (K108/K109) as a metabolically triggered switch that disassembles V-ATPase, alkalinizes lysosomes, and initiates Cathepsin B–mediated mitochondrial ROS leading to caspase-8/3/GSDME-dependent pyroptosis. An AAV-delivered lactylation-deficient ATP6V1B2 mutant (2KR) blocked this cascade and reduced airway inflammation in vivo.

Key Findings

• Quantitative lactylomics identified ATP6V1B2 K108/K109 lactylation as a core modification in HDM-induced asthma.
• ATP6V1B2 lactylation disassembled the V1–V0 V-ATPase complex, causing lysosomal alkalinization and membrane permeabilization.
• LMP triggered Cathepsin B–mediated mitochondrial ROS bursts that initiated non-canonical caspase-8/3/GSDME-dependent pyroptosis.
• An AAV-delivered lactylation-deficient ATP6V1B2 (2KR) mutant reduced airway inflammation, Th2 cytokines, and tissue pyroptosis in vivo.
• Lactylation was validated in primary human bronchial epithelial cells following HDM and l-lactate stimulation.

Clinical Implications

While preclinical, targeting ATP6V1B2 lactylation or its downstream LMP–ROS–GSDME axis could offer a novel anti-inflammatory strategy for severe, metabolically dysregulated asthma.

Limitations

• Preclinical study without human clinical outcome data
• Potential heterogeneity of asthma endotypes may limit generalizability; off-target effects of AAV or lactylation modulation require evaluation

Future Directions

Validate ATP6V1B2 lactylation as a biomarker in patient airway samples, develop small-molecule or biologic inhibitors of the lactylation event, and test efficacy-safety in translational models moving toward early-phase clinical trials.