Exploring IDH2 as a therapeutic target:in silico and in vitro evidence for the potential of cobicistat and licorice glycoside E in sepsis-associated complicationsOA

Background:Sepsis,a life-threatening systemic inflammatory response to infection,presents significant challenges in the intensive care unit(ICU).The condition is frequently accompanied by persistent neurodegenerative changes and muscle atrophy,especially in patients with burn wounds,severely affecting recuperation and quality of life.Traditional physical therapy and advanced sedative screening represent pivotal approaches for the rehabilitation and management of these cases.Methods:A comprehensive transcriptomic study was conducted using gene expression datasets from sepsis patients and important biological models to identify potential targets.We subsequently employed virtual molecular docking and molecular dynamics simulations to screen the FDA drug library and traditional Chinese medicine databases for compounds exhibiting high binding affinity to isocitrate dehydrogenase 2(IDH2).The functional role of this target was validated in vitro using an IDH2 deficient BV-2 microglial cell model stimulated by lipopolysaccharide.Results:Key features were identified through differential expression analysis across multiple datasets.Gene set enrichment analysis(GSEA)highlighted pathways associated with chronic neurodegenerative diseases.Stable interactions between IDH2 and cobicistat or licorice glycoside E were predicted,supporting the identification of IDH2 as a promising therapeutic target.Knockdown of IDH2 in microglial cells led to markedly suppressed production of pro-inflammatory cytokines,including TNF-αand IL-6,confirming its pivotal role in neuroinflammatory response regulation.Conclusion:These findings underscore the pivotal role of IDH2 in persistent neurodegenerative changes associated with sepsis,including burn-related cases.Targeting IDH2 may reduce long-term neurovascular complications and muscle atrophy in septic ICU patients.Our findings suggest that IDH2 is a potential therapeutic target,and the combination of cobicistat and licorice glycoside E warrants further investigation as a promising therapeutic strategy.The study also emphasizes the significance of novel neuroinflammatory and neurovascular biomarkers in understanding and managing long-term sequelae in septic survivors.