Exploration potential sepsis–ferroptosis mechanisms through the use of CETSA technology and network pharmacology

As an important self-protection response mechanism of the body, inflammation can not only remove the necrotic or even malignant cells in the body, but also take a series of targeted measures to eliminate the pathogen of foreign invasion and block the foreign substances that may affect the life and health of the body. Flavonoids have known anti-inflammatory, anti-oxidation, anti-cancer and other effects, including glycyrrhizin molecules is one of the representatives. Licochalcone D has known anti-inflammatory and antioxidant properties and is effective in the treatment of a variety of inflammatory diseases. However, the underlying mechanism for the treatment of sepsis remains unclear. In this study, the therapeutic potential of Licochalcone D for sepsis was studied by analyzing network pharmacology and molecular dynamics simulation methods. Sepsis-related genes were collected from the database to construct PPI network maps and drug-targeting network profiles. The potential mechanism of Licochalcone D in sepsis was predicted by gene ontology, KEGG and molecular dynamics simulation. Sixty drug-disease genes were subsequently validated. Go analysis showed that monomeric small molecule Licochalcone D could regulate the process of intracellular enzyme system. The KEGG pathway analysis showed that the signal pathway of the main effect was related to the calcium pathway. The results of intersections with iron death-related target genes showed that ALOX5, ALOX15B and other nine targets all had the effect of possibly improving sepsis, while GSE 54,514, GSE 95,233 and GSE 69,528 were used to analyze the survival rate and ROC curve. Five genes were screened, including ALOX5, ALOX15B, NFE2L2 and NR4A1, HIF1A. The results of molecular docking showed that ALOX5 and Licochalcone D had strong binding activity. Finally, the results of molecular dynamics simulation showed that there was good binding power between drug and target. In the present study, we utilized molecular dynamics simulation techniques to assess the binding affinity between the small-molecule ligand and the protein receptor. The simulation outcomes demonstrate that the binding interface between the ligand and receptor remains stable, with a calculated binding free energy (ΔG) of -32.47 kJ/mol. This signifies a high-affinity interaction between the ligand and receptor, suggesting the long-term stability of the small molecule under physiological conditions. These findings provide critical insights for drug development efforts. This study elucidates the therapeutic potential of Licochalcone D, a traditional Chinese medicine monomer, in improving sepsis through the regulation of ferroptosis, thereby providing a new direction and option for subsequent clinical drug development in the treatment of sepsis.