PPARγ agonist alleviates sepsis-related liver injury by modulating M1/M2 macrophage polarization via the...

Sepsis-related liver injury (SRLI) results from sepsis and can lead to abnormal liver function, biochemical changes, or liver failure, with limited treatment options. This study analyzed two GEO datasets (GSE139602 and GSE57065) to identify genes associated with SRLI using weighted gene co-expression network analysis (WGCNA), focusing on peroxisome proliferator-activated receptor gamma (PPARγ). The therapeutic effects of pioglitazone, a PPARγ agonist, were investigated in SRLI through modulation of macrophage polarization in vivo and in vitro. A rat SRLI model was established using cecal ligation and puncture (CLP), and the study included control, CLP, CLP + pioglitazone (Pio), and CLP + GW9662 (PPARγ inhibitor) groups. Biochemical indices, pathological changes, flow cytometry, and transcriptomics were used to assess pioglitazone's effects. Additionally, RAW264.7 cells were employed to explore the underlying mechanisms in vitro. PPARγ was identified as a key gene linked to SRLI. In vivo, pioglitazone treatment promoted Kupffer cell polarization towards the M2 phenotype, reducing inflammatory cytokines and alleviating liver damage and systemic inflammation. Transcriptomic analysis revealed 1234 genes were no longer significantly upregulated in the CLP + Pio group compared to the CLP group. KEGG pathway enrichment analysis highlighted IκBα and NF-κB signaling via GSEA. In vitro, pioglitazone further facilitated M2 macrophage polarization. Molecular docking and western blotting confirmed that pioglitazone inhibits the PPARγ/IκBα/NF-κB pathway both in vitro and in vivo. Activation of PPARγ alleviates SRLI in rats by modulating M1/M2 macrophage polarization through the PPARγ/IκBα/NF-κB pathway.