Abstract
INTRODUCTION: Sepsis-induced acute lung injury (ALI), a critical sequela of systemic inflammation, often progresses to acute respiratory distress syndrome, conferring high mortality. Although UMI-77 has demonstrated efficacy in mitigating lung injury in sepsis, the molecular mechanisms underlying its action have not yet been fully elucidated. METHODS: This study aimed to delineate the mechanism by which UMI-77 counteracts sepsis-induced ALI using comprehensive transcriptomic and metabolomic analyses. RESULTS: UMI-77 significantly ameliorated histopathological changes in the lungs of mice with sepsis-induced ALI Transcriptomic analysis revealed that 124 differentially expressed genes were modulated by UMI-77 and were predominantly implicated in chemokine-mediated signaling pathways, apoptosis regulation, and inflammatory responses. Integrated metabolomic analysis identified Atp4a, Ido1, Ctla4, and Cxcl10 as key genes, and inosine 5'-monophosphate (IMP), thiamine monophosphate, thymidine 3',5'-cyclic monophosphate (dTMP) as key differential metabolites. UMI-77 may regulate key genes (Atp4a, Ido1, Ctla4, and Cxcl10) to affect key metabolites (IMP, thiamine monophosphate, and dTMP) and their target genes (Entpd2, Entpd1, Nt5e, and Hprt) involved in cytokine-cytokine receptor interaction, gastric acid secretion, pyrimidine, and purine metabolism in the treatment of sepsis-induced ALI. CONCLUSION: UMI-77 exerts its therapeutic effect in sepsis-induced ALI through intricate modulation of pivotal genes and metabolites, thereby influencing critical biological pathways. This study lays the groundwork for further development and clinical translation of UMI-77 as a potential therapeutic agent for sepsis-associated lung injuries.