Local lactate-driven H3K18 lactylation impairs anti-influenza immunity through NRF2-dependent dendritic cell dysfunction.

Authors

Chen Lyu, Jiuyang Xu, Yulin Zhang, Fei Zhu, Di He, Weiwei Ge, Congcong Shang, Qi Wang, Wenting Zuo, Yingying Yuan, Yawen Ni, Yitian Xu, Ziyao Li, Yuxian Mu, Rongling Zhang, Bin Cao

Published in

Cell reports. Volume 45. Issue 9. Pages 117943. Sep 03, 2026. Epub Sep 03, 2026.

Abstract

Metabolic alterations are increasingly recognized during influenza virus infection, but how local lactate accumulation shapes antiviral immunity remains poorly characterized. By integrating time-series targeted energy metabolomics, single-cell RNA sequencing, flow cytometry, and functional perturbation, we show that influenza virus infection preferentially increases lactate within the lung microenvironment, where it restrains pulmonary CD8⁺ T cell response. Mechanistically, extracellular lactate enters dendritic cells through monocarboxylate transporter (MCT)-dependent transport and induces a tolerogenic-like state marked by impaired maturation, reduced costimulation, and diminished CD8⁺ T cell-priming capacity. Direct experimental evidence identifies H3K18la as a prominent lactate-responsive histone lactylation mark, while multi-omics integration links it to enhancer accessibility and NRF2 pathway activation. Functional studies further show that NRF2 promotes dendritic cell suppression by reinforcing tolerogenic programs and limiting mtROS-dependent XBP1 splicing. Together, these findings reveal a lactate-driven histone lactylation-NRF2 pathway that modulates antiviral immunity during influenza infection.

PMID:
42690934
Bibliographic data and abstract were imported from PubMed on 04 Sep 2026.

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