Advanced glycation end products exacerbate lipopolysaccharide-induced acute lung injury with diabetes by promoting ferroptosis via AMP-activated protein kinase/acetyl-CoA carboxylase signaling

Abstract

Abstract Diabetes increases susceptibility to acute lung injury (ALI), yet the mechanisms linking hyperglycemia to pulmonary damage remain incompletely understood. Here, we demonstrate advanced glycation end products (AGEs)—metabolic byproducts elevated in diabetes—as promoters of ferroptosis that contribute to ALI pathogenesis. Clinical analysis of 170 patients with sepsis-related ALI showed that diabetic individuals had heightened inflammation and reduced PaO₂/FiO₂ ratios. Bioinformatic analysis revealed overlapping ferroptosis-related gene signatures between DM and ALI. In lipopolysaccharide (LPS)-induced ALI mice with diabetes mellitus (DM), reducing AGEs levels attenuated inflammatory cell infiltration and pro-inflammatory cytokine production, decreased Fe²⁺ accumulation and malondialdehyde (MDA) levels, and increased the expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). In vitro experiments suggested that AGEs exacerbate ferroptotic injury in LPS-treated bronchial epithelial (BEAS-2B) cells partly by suppressing AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) signaling, an effect mitigated by pharmacological AMPK activation. These findings support a potential mechanistic link between DM and ALI through AGEs-driven ferroptosis and raise the possibility that targeting the AMPK/ACC pathway could offer therapeutic benefit.