Therapeutic Potential of Inhibiting Hmox1 in Sepsis-Induced Lung Injury: A Molecular Mechanism Study

Abstract

Sepsis induces severe multiorgan dysfunction, with the lungs being particularly susceptible to damage. This study reveals that Hmox1 inhibitors effectively activate the FSP1/CoQ10/NADPH pathway, significantly enhancing autophagic activity while suppressing ferroptosis in alveolar epithelial cells, thereby alleviating lung injury in septic mice. To identify key gene modules and regulatory factors associated with sepsis-induced lung injury, we analyzed public transcriptomic data, including bulk RNA-seq datasets (GSE236391 and GSE263867) and a single-cell RNA-seq (scRNA-seq) data set (GSE207651). In vitro experiments were conducted using an LPS-induced alveolar epithelial cell injury model to evaluate the effects of Hmox1 inhibitors on cell viability, autophagy markers (LC3-II/LC3-I and p62), ROS levels, and intracellular iron content. Transmission electron microscopy was used to observe mitochondrial structural changes. In vivo, a cecal ligation and puncture (CLP)-induced sepsis mouse model was established to assess the therapeutic effects of Hmox1 inhibitors. This included evaluating survival rates, lung histopathological scores, lung wet-to-dry weight ratios, myeloperoxidase (MPO) activity, inflammatory cytokine levels, and changes in autophagy and ferroptosis markers. The results demonstrated that Hmox1 inhibitors effectively mitigate lung injury by modulating the autophagy-ferroptosis pathway, highlighting their potential as a therapeutic strategy for sepsis-induced lung damage.