PDK4-driven lactate accumulation facilitates LPCAT2 lactylation to exacerbate sepsis-induced acute lung injury

Elevated glycolysis in lung tissue is a hallmark of sepsis-induced acute lung injury (SI-ALI), yet the role of glycolytic reprogramming and lactate-derived protein modifications in damaging epithelial cells remains poorly understood. In this study, we reveal that PDK4-driven glycolytic reprogramming promotes excessive lactate production in lung tissue during SI-ALI. Mechanistically, AARS1 in epithelial cells selectively enhances lactylation modification at the K375 site of LPCAT2, which suppresses STAT1 acetylation and facilitates STAT1 phosphorylation, nuclear translocation, and transcriptional repression of SLC7A11. This cascade ultimately triggers epithelial cells Ferroptosis. Pharmacological inhibition of PDK4 attenuates lactate accumulation and LPCAT2 lactylation, thereby restoring STAT1 acetylation and SLC7A11 expression. Furthermore, AARS1 knockdown or mutation of the LPCAT2-K375 lactylation site rescues STAT1-mediated SLC7A11 suppression and mitigates Ferroptosis in vitro and septic mice. Our findings revealed that elevated expression of PDK4 is a critical factor contributing to the increased lactate production in lung tissue during sepsis, and established a novel LPCAT2-K375/STAT1/SLC7A11 axis driving epithelial cells Ferroptosis in SI-ALI, highlighting the crosstalk between metabolic reprogramming, post-translational modifications (PTM), and Ferroptosis. Targeting the PDK4 or LPCAT2 lactylation may offer therapeutic potential for SI-ALI. In sepsis-induced acute lung injury (SI-ALI), PDK4 hyperactivation drives excessive lactate production in epithelial cells, triggering AARS1/HDAC9-mediated LPCAT2 lactylation. This modification suppresses STAT1 acetylation while enhancing phosphorylation, driving its nuclear translocation and subsequent SLC7A11 transcriptional downregulation. The resultant glutathione synthesis deficiency promotes Ferroptosis, exacerbating SI-ALI progression.