Diabetes mellitus aggravates sepsis-induced lung injury by triggering NPM3-ACSL1 pathway-mediated ferroptosis

Hyperglycemia is a poor prognostic factor in critically ill septic patients with diabetes. Acute lung injury (ALI) resulting from hyperglycemia combined with sepsis remains an urgent clinical challenge. However, the mechanisms by which hyperglycemia contributes to sepsis-associated ALI remain unclear. In this study, we investigate the molecular mechanisms through which hyperglycemia accelerates ALI and mortality in sepsis using in vivo and in vitro models. High NPM3 expression not only mediates H3K18la levels but also promotes its binding to the ACSL1 promoter. Elevated ACSL1 expression and abnormal subcellular organelle localization disrupt lipid metabolism in macrophages, ultimately leading to ferroptosis. Our findings indicate that hyperglycemia enhances ferroptosis via the NPM3-H3K18la-ACSL1 axis in macrophages during sepsis-associated ALI. Targeted inhibition of this axis effectively suppresses hyperglycemia-induced ferroptosis in macrophages and reduces ALI and mortality in septic mice. Thus, targeting the NPM3-H3K18la-ACSL1 axis represents a promising therapeutic strategy for hyperglycemic/diabetic patients with sepsis-associated ALI.