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.
Department of Cardiac Surgery, The Ohio State University, Columbus, USA.
Redox Biol. 2024 Aug;74:103194. doi: 10.1016/j.redox.2024.103194. Epub 2024 May 16.
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.
乳酸水平升高是脓毒症的一个重要生物标志物，与脓毒症相关死亡率呈正相关。脓毒症相关性肺损伤（ALI）是临床患者预后不良的主要原因。然而，乳酸在脓毒症相关性 ALI 中的作用机制尚不清楚。在这项研究中，我们证明乳酸通过促进 p300 介导的 H3K18la 与 METTL3 启动子位点的结合来调节 N6-甲基腺苷（m6A）修饰水平。METTL3 介导的 m6A 修饰在 ACSL4 中富集，其 mRNA 稳定性通过 YTHDC1 依赖性途径进行调节。此外，短期乳酸刺激上调 ACSL4，促进与线粒体相关的铁死亡。通过敲低或靶向抑制 METTL3 可有效抑制肺泡上皮细胞中脓毒症高乳酸诱导的铁死亡，并减轻脓毒症小鼠的肺损伤。我们的研究结果表明，在脓毒症相关性 ALI 期间，乳酸通过 GPR81/H3K18la/METTL3/ACSL4 轴诱导肺泡上皮细胞中的铁死亡。这些结果揭示了一种通过 METTL3 介导的 m6A 修饰诱导铁死亡的组蛋白乳酰化驱动机制。靶向 METTL3 可能为脓毒症相关性 ALI 患者提供一种有前途的治疗策略。
