Histone lactylation-regulated METTL3 promotes ferroptosis via m6A-modification on ACSL4 in sepsis-associated lung injury

  • Redox Biol. 2024 Aug:74:103194. doi: 10.1016/j.redox.2024.103194.
Dan Wu  1 ,  Charles B Spencer  2 ,  Lilibeth Ortoga  3 ,  Hao Zhang  4 ,  Changhong Miao  5
Affiliations
  • 1. Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China; Department of Anesthesiology, Shanghai Medical College, Fudan University, China.
  • 2. Department of Cardiac Surgery, The Ohio State University, Columbus, USA.
  • 3. Department of Biomedical Engineering, The Ohio State University, Columbus, USA.
  • 4. Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China; Department of Anesthesiology, Shanghai Medical College, Fudan University, China. Electronic address: [email protected].
  • 5. Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China; Department of Anesthesiology, Shanghai Medical College, Fudan University, China. Electronic address: [email protected].
PMID: 38852200 DOI: 10.1016/j.redox.2024.103194
Abstract

Elevated lactate levels are a significant biomarker of sepsis and are positively associated with sepsis-related mortality. Sepsis-associated lung injury (ALI) is a leading cause of poor prognosis in clinical patients. However, the underlying mechanisms of lactate's involvement in sepsis-associated ALI remain unclear. In this study, we demonstrate that lactate regulates N6-methyladenosine (m6A) modification levels by facilitating p300-mediated H3K18la binding to the METTL3 promoter site. The METTL3-mediated m6A modification is enriched in ACSL4, and its mRNA stability is regulated through a YTHDC1-dependent pathway. Furthermore, short-term lactate stimulation upregulates ACSL4, which promotes mitochondria-associated Ferroptosis. Inhibition of METTL3 through knockdown or targeted inhibition effectively suppresses septic hyper-lactate-induced Ferroptosis in alveolar epithelial cells and mitigates lung injury in septic mice. Our findings suggest that lactate induces Ferroptosis via the GPR81/H3K18la/METTL3/ACSL4 axis in alveolar epithelial cells during sepsis-associated ALI. These results reveal a histone lactylation-driven mechanism inducing Ferroptosis through METTL3-mediated m6A modification. Targeting METTL3 represents a promising therapeutic strategy for patients with sepsis-associated ALI.

Keywords
Ferroptosis; Histone lactylation; N6- methyladenosine; Sepsis-associated acute lung injury.
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