Background <p>Renal fibrosis is a progressive injury contributing to renal function deterioration. Mounting evidence has underscored the profound impact of gut microbiota metabolites on host health and disease, yet their underlying mechanisms against renal fibrosis remain unclear. The aim of this study was to fully elucidate their therapeutic potential in the context of renal fibrosis.</p> Methods <p>The targets of gut microbiota metabolites were identified in gutMGene. The diseases targets were obtained from the OMIM, GeneCards and DisGeNet databases. The STRING and DAVID platform were employed to identify the core targets and pathways. Gut Microbiota-Targets-Pathway-Metabolites (G-T-P-M) network was constructed to screen the core metabolites. Molecular docking was used to assess the interactions between the targets and metabolites.</p> Results <p>A total of 47 overlapping targets related to gut microbiota metabolites and renal fibrosis were acquired. The bioinformatics analysis indicated that the targets were enriched in the regulation of TNF pathway and Toll-like receptor pathway. The PPI network (Protein-Protein Interaction) identified JUN, IL6, IL1B and AKT1 as the core targets. The G-T-P-M network revealed that Propionate, Butyrate and 3-Indolepropionic acid were identified as the core non-toxic and promising core metabolites. The core metabolites showed stable binding affinity with the core targets.</p> Conclusion <p>The findings highlight that gut microbiota metabolites represent a promising therapeutic option for combating renal fibrosis by modulating multiple targets and pathways, providing a theoretical foundation for the future studies exploring gut microbiota as targeted strategies in the prevention and treatment of renal fibrosis.</p> Graphical abstract <p></p>