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.

中文翻译：

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组蛋白乳酰化调节的 METTL3 通过 ACSL4 上的 m6A 修饰促进脓毒症相关肺损伤中的铁死亡


乳酸水平升高是脓毒症的重要生物标志物，并且与脓毒症相关死亡率呈正相关。脓毒症相关肺损伤（ALI）是临床患者预后不良的主要原因。然而，乳酸参与脓毒症相关 ALI 的潜在机制仍不清楚。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，短期乳酸刺激会上调 ACSL4，从而促进线粒体相关的铁死亡。通过敲低或靶向抑制来抑制 METTL3 可有效抑制脓毒症高乳酸诱导的肺泡上皮细胞铁死亡，并减轻脓毒症小鼠的肺损伤。我们的研究结果表明，在脓毒症相关的 ALI 期间，乳酸通过肺泡上皮细胞中的 GPR81/H3K18la/METTL3/ACSL4 轴诱导铁死亡。这些结果揭示了组蛋白乳酰化驱动的机制，通过 METTL3 介导的 m6A 修饰诱导铁死亡。针对脓毒症相关 ALI 患者，靶向 METTL3 是一种有前景的治疗策略。