Lactate regulates N6-methyladenosine (m6A) modification levels by facilitating p300-mediated H3K18la binding to the METTL3 promoter site. METTL3-mediated m6A modification is enriched in ACSL4, and its mRNA stability is regulated through a YTHDC1-dependent pathway. Short-term lactate stimulation upregulates ACSL4, promoting mitochondria-associated ferroptosis. Inhibition of METTL3 suppresses septic hyper-lactate-induced ferroptosis in alveolar epithelial cells and mitigates lung injury in septic mice. The study reveals that lactate induces ferroptosis via the GPR81/H3K18la/METTL3/ACSL4 axis in alveolar epithelial cells during sepsis-associated acute lung injury (ALI). These findings highlight 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. Lactate levels are a significant biomarker of sepsis and are positively associated with sepsis-related mortality. Sepsis-associated ALI is a leading cause of poor prognosis in clinical patients. The study demonstrates that lactate regulates m6A modification by promoting p300-mediated H3K18la binding to the METTL3 promoter site. METTL3-mediated m6A modification is enriched in ACSL4, and its mRNA stability is regulated through a YTHDC1-dependent pathway. Short-term lactate stimulation upregulates ACSL4, promoting mitochondria-associated ferroptosis. Inhibition of METTL3 suppresses septic hyper-lactate-induced ferroptosis in alveolar epithelial cells and mitigates lung injury in septic mice. The study reveals that lactate induces ferroptosis via the GPR81/H3K18la/METTL3/ACSL4 axis in alveolar epithelial cells during sepsis-associated ALI. These findings highlight 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.Lactate regulates N6-methyladenosine (m6A) modification levels by facilitating p300-mediated H3K18la binding to the METTL3 promoter site. METTL3-mediated m6A modification is enriched in ACSL4, and its mRNA stability is regulated through a YTHDC1-dependent pathway. Short-term lactate stimulation upregulates ACSL4, promoting mitochondria-associated ferroptosis. Inhibition of METTL3 suppresses septic hyper-lactate-induced ferroptosis in alveolar epithelial cells and mitigates lung injury in septic mice. The study reveals that lactate induces ferroptosis via the GPR81/H3K18la/METTL3/ACSL4 axis in alveolar epithelial cells during sepsis-associated acute lung injury (ALI). These findings highlight 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. Lactate levels are a significant biomarker of sepsis and are positively associated with sepsis-related mortality. Sepsis-associated ALI is a leading cause of poor prognosis in clinical patients. The study demonstrates that lactate regulates m6A modification by promoting p300-mediated H3K18la binding to the METTL3 promoter site. METTL3-mediated m6A modification is enriched in ACSL4, and its mRNA stability is regulated through a YTHDC1-dependent pathway. Short-term lactate stimulation upregulates ACSL4, promoting mitochondria-associated ferroptosis. Inhibition of METTL3 suppresses septic hyper-lactate-induced ferroptosis in alveolar epithelial cells and mitigates lung injury in septic mice. The study reveals that lactate induces ferroptosis via the GPR81/H3K18la/METTL3/ACSL4 axis in alveolar epithelial cells during sepsis-associated ALI. These findings highlight 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.