Dimethyl fumarate improves sepsis-induced acute lung injury by inhibiting STING-mediated ferroptosis

The precise pathogenic mechanisms underlying sepsis-induced acute respiratory distress syndrome (ARDS) remain incompletely characterized. Emerging evidence implicates Ferroptosis of alveolar epithelial cells in ARDS pathogenesis, though the regulatory networks governing this association require further elucidation. Stimulator of interferon genes (STING), conventionally recognized as a pivotal mediator of innate immunity through DNA-sensing pathways, has recently been linked to Ferroptosis. This investigation elucidates the pulmonary protective mechanisms of DMF in sepsis-induced ALI models. Experimental data revealed elevated ferroptotic activity, inflammatory markers, and oxidative stress in lungs following cecal ligation and puncture (CLP) procedures. DMF administration significantly attenuated pulmonary Ferroptosis while concurrently mitigating inflammation and oxidative damage, ultimately ameliorating histological lung injury. Complementary in vitro studies demonstrated DMF's capacity to suppress lipopolysaccharide (LPS)-induced Ferroptosis in MLE-12 cells. Mechanistic analyses identified dual protective pathways. DMF not only inhibited LPS-triggered STING activation and subsequent proinflammatory cytokine production but also prevented STING-mediated autophagic degradation of Glutathione Peroxidase 4 (GPX4). This dual action effectively reduced Reactive Oxygen Species (ROS) accumulation and ferroptotic cell death. These findings position DMF as a promising therapeutic candidate with dual pharmacological actions - functioning as both a STING pathway inhibitor and Ferroptosis suppressor.

Acute respiratory distress syndrome; Dimethyl fumarate; Ferroptosis; GPX4; STING; Sepsis.