HIF-1 A-Mediated Lactate Metabolism Confers Ferroptosis Resistance in M1 Macrophages Through Histone Lactylation During Acute Lung Injury

Background: Acute lung injury (ALI) is characterized by excessive inflammation and oxidative stress, with macrophages playing pivotal roles in disease progression. The differential survival mechanisms of macrophage subsets during ALI remain poorly understood. Methods: We performed integrated analysis of ALI datasets (GSE11434, GSE237260, GSE264032) and isolated CD14 + macrophages from bronchoalveolar lavage fluid of ALI patients. Murine alveolar macrophages (MH-S) were polarized to M1/M2 phenotypes and subjected to ferroptosis induction. HIF-1 A knockdown and lactate supplementation experiments were performed to investigate metabolic regulation. Myeloid-specific HIF-1 A knockout mice were generated and subjected to LPS-induced ALI. Results: Transcriptomic analysis revealed ferroptosis as a key pathway in ALI, with macrophages showing the highest expression of ferroptosis-related genes. ALI-derived macrophages exhibited enhanced ferroptosis-defense gene expression and elevated lactate production. M1 macrophages demonstrated superior ferroptosis resistance compared to M2 macrophages, associated with higher baseline expression of antioxidant genes and enhanced HIF-1 A signaling. Mechanistically, HIF-1 A in M1 macrophages promoted lactate metabolism, which activated ferroptosis-defense genes through histone lactylation. Myeloid-specific HIF-1 A knockout prevented M1 macrophage survival advantage, reduced inflammatory tissue damage, and alleviated ALI severity. Conclusions: HIF-1 A-mediated lactate metabolism confers ferroptosis resistance in M1 macrophages through epigenetic activation of antioxidant defense genes. This metabolic reprogramming represents a novel therapeutic target for modulating macrophage survival and inflammation in ALI.