2. Academic Validation
  3. Lactylation-YTHDF1 Axis Promotes DNAH5-dependent Ciliary Defense in Pseudomonas aeruginosa Infection

Lactylation-YTHDF1 Axis Promotes DNAH5-dependent Ciliary Defense in Pseudomonas aeruginosa Infection

  • Am J Respir Cell Mol Biol. 2026 Jan 23:aanaf010. doi: 10.1093/ajrcmb/aanaf010.
Jing Wang 1 2 3,  Xiang Shen 1 2 3,  Yanan Li 1 2 3,  Zhenwei Xia 4,  Tong Yin 5,  Jing Qiao 5,  Yangyang Deng 1 2 3,  Runying He 1 2 3,  Yu Guo 1 2 3,  Yuxuan Zhang 1 2 3,  Guoliang Zhang 1 2 3,  Jieming Qu 1 2 3
Affiliations

Affiliations

  • 1 Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 2 Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 3 Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases, Shanghai 200025, China.
  • 4 Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 5 Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
PMID: 41738162 DOI: 10.1093/ajrcmb/aanaf010
Abstract

Pseudomonas aeruginosa Infection poses a significant clinical challenge in respiratory diseases by subverting host defense mechanisms. While inflammatory responses in airway epithelial cells (AECs) during Infection have been extensively studied, the interplay between epitranscriptomic regulation and metabolic reprogramming remains poorly understood. Here, we identify a lactylation-m6A axis that orchestrates ciliary function and Antibacterial defense through dual-layer metabolic-epigenetic coordination. Using integrated in vivo and in vitro models, we demonstrate that P. aeruginosa Infection depletes host lactic acid through direct consumption via Lactate Dehydrogenase and virulence factor-mediated glycolytic suppression. This metabolic perturbation reduces histone H3K18 lactyaltion, dimishing m6A methylation by directly downregulating YTHDF1; m6A-seq analysis reveals preferential hypomethylation of dynein axonemal heavy chain 5 (DNAH5) mRNA, a critical regulator of ciliary motility. Mechanistically, YTHDF1 recognizes m6A-modified DNAH5 transcripts to stabilize translation. The lactylation-YTHDF1-DNAH5 axis proves essential for maintaining ciliary beat frequency and mucociliary clearance capacity. This metabolic-epitranscriptomic circuitry significantly impacts host defense, as evidenced by increased Bacterial burden in conditional YTHDF1 knockout mice. Our findings extend the paradigm of lactylation-mediated gene regulation to airway pathophysiology, revealing a novel mechanism where microbial-induced metabolic perturbations reprogram RNA modification landscapes to disable ciliary defenses. This study establishes a conceptual framework for understanding how opportunistic pathogens exploit host metabolic-epigenetic networks to establish persistent infections, suggesting therapeutic potential for targeting the lactate-YTHDF1 axis in P. aeruginosa-associated pulmonary disorders.

Keywords

Pseudomonas Aeruginosa; Ciliary Beating; Lactylation; YTHDF1; m6A Modification.

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