AARS1-Mediated RUNX3 K193 Lactylation Enhances the Activation and Cytotoxicity of CD8+T Cells in Smoking-Related Emphysema.

Emphysema is the primary pathological feature of chronic obstructive pulmonary disease (COPD). The accumulation of CD8+T cells induces epithelial cell damage, thereby impairing the pulmonary alveolar niche. In this study, we demonstrated that CD8+T cell activation was associated with COPD progression. Furthermore, our data indicated that AARS1-mediated lactylation was involved in cigarette smoke extract (CSE)-induced CD8+T cell activation. Mechanistically, cigarette smoke (CS) exposure upregulated AARS1 levels in CD8+T cells. Elevated AARS1 catalyzed the transfer of a lactyl group to RUNX3 at the K193 site, leading to the elevation of lactylation of RUNX3-K193, and inhibited RUNX3 fusion with autophagosomes for degradation. Subsequent accumulation of RUNX3 promoted CD8+T cell activation and enhanced their cytotoxicity. Here we demonstrate, using a CD8+T cell-lung organoid co-culture model and an experimental emphysema model induced by CS, that treatment with the lactate inhibitor DCA and silencing of AARS1 abrogated CS-induced CD8+T cell activation, which ameliorated emphysematous pathological changes in mouse lung tissue. Moreover, elevated lactate and AARS1 negatively correlated with lung function in human populations. Collectively, this study reveals that AARS1 drives CD8+T cell activation by mediating RUNX3 lactylation to inhibit its autolysosomal degradation, and targeting of AARS1 may provide new insights into the therapy of emphysema.