This study investigates the role of lactate in sepsis-associated acute lung injury (ALI) and its mechanism of action. High lactate levels are associated with poor prognosis and mortality in sepsis patients. The study demonstrates that lactate regulates N6-methyladenosine (m6A) modification by facilitating p300-mediated H3K18a binding to the METTL3 promoter site. METTL3-mediated m6A modification is enriched in ACSL4, influencing its mRNA stability through a YTHDC1-dependent pathway. Short-term lactate stimulation upregulates ACSL4, promoting mitochondria-associated ferroptosis. Inhibition of METTL3 through knockdown or pharmacological intervention effectively ameliorates sepsis-induced lung injury and ferroptosis in alveolar epithelial cells, reducing lung injury in septic mice. The findings suggest that lactate induces ferroptosis via the GPR81/H3K18a/METTL3/ACSL4 axis in alveolar epithelial cells during sepsis-associated ALI, highlighting the potential of targeting METTL3 as a therapeutic strategy.This study investigates the role of lactate in sepsis-associated acute lung injury (ALI) and its mechanism of action. High lactate levels are associated with poor prognosis and mortality in sepsis patients. The study demonstrates that lactate regulates N6-methyladenosine (m6A) modification by facilitating p300-mediated H3K18a binding to the METTL3 promoter site. METTL3-mediated m6A modification is enriched in ACSL4, influencing its mRNA stability through a YTHDC1-dependent pathway. Short-term lactate stimulation upregulates ACSL4, promoting mitochondria-associated ferroptosis. Inhibition of METTL3 through knockdown or pharmacological intervention effectively ameliorates sepsis-induced lung injury and ferroptosis in alveolar epithelial cells, reducing lung injury in septic mice. The findings suggest that lactate induces ferroptosis via the GPR81/H3K18a/METTL3/ACSL4 axis in alveolar epithelial cells during sepsis-associated ALI, highlighting the potential of targeting METTL3 as a therapeutic strategy.