AARS1‐Mediated RUNX3 K193 Lactylation Enhances the Activation and Cytotoxicity of CD8+T Cells in Smoking‐Related Emphysema
4 affiliations
- 1Center For Global Health The Key Laboratory of Modern Toxicology Ministry of Education School of Public Health Suzhou Institute for Advanced Study of Public Health Gusu School Nanjing Medical University Nanjing Jiangsu People's Republic of China
- 2Department of Respiratory and Critical Care Medicine The Affiliated Wuxi People's Hospital of Nanjing Medical University Wuxi Medical Center Nanjing Medical University Wuxi Jiangsu People's Republic of China
- 3Department of Respiratory and Critical Care Medicine The Affiliated Suzhou Hospital of Nanjing Medical University Suzhou Municipal Hospital Nanjing Medical University Suzhou Jiangsu People's Republic of China
- 4Animal Core Facility Jiangsu Animal Experimental Center of Medical & Pharmaceutical Research Nanjing Medical University Nanjing Jiangsu People's Republic of China
Abstract
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.
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BibTeX
@article{zhu2026aars1mediated,
title = {{AARS1‐Mediated RUNX3 K193 Lactylation Enhances the Activation and Cytotoxicity of CD8+T Cells in Smoking‐Related Emphysema}},
author = {Ying Zhu and Jiaheng Lin and Yifan Li and Qiaoqiao Zhou and Min Yu and Cheng Cheng and Kang Chang and Dang Lin and Tao Bian and Yan Wu and Lu Lu and Haibo Xia and Qizhan Liu},
journal = {Advanced Science},
year = {2026},
month = aug,
doi = {10.1002/advs.76949},
url = {https://doi.org/10.1002/advs.76949},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - AARS1‐Mediated RUNX3 K193 Lactylation Enhances the Activation and Cytotoxicity of CD8+T Cells in Smoking‐Related Emphysema
AU - Ying Zhu
AU - Jiaheng Lin
AU - Yifan Li
AU - Qiaoqiao Zhou
AU - Min Yu
AU - Cheng Cheng
AU - Kang Chang
AU - Dang Lin
AU - Tao Bian
AU - Yan Wu
AU - Lu Lu
AU - Haibo Xia
AU - Qizhan Liu
PY - 2026
DA - 2026/08/06
JO - Advanced Science
DO - 10.1002/advs.76949
UR - https://doi.org/10.1002/advs.76949
AB - 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.
SN - 2198-3844
ER -