A sumoylation-dependent pathway mediates transrepression of inflammatory response genes by PPARγ. PPARγ, a key regulator of adipogenesis and glucose homeostasis, is a target of insulin-sensitizing drugs. While PPARγ agonists are known to suppress inflammatory responses by transrepressing NF-κB target genes, the underlying mechanisms remain unclear. This study identifies a molecular pathway by which PPARγ represses the transcriptional activation of inflammatory genes in macrophages. The process begins with ligand-dependent sumoylation of the PPARγ ligand-binding domain, which targets PPARγ to NCoR/HDAC3 complexes on inflammatory gene promoters. This prevents the recruitment of ubiquitylation/19S proteosome machinery, which normally removes corepressor complexes required for gene activation. As a result, NCoR complexes remain bound to the promoter, maintaining target genes in a repressed state. NCoR and SMRT are components of corepressor complexes containing HDAC3, TBL1, and TBLR1 that interact with unliganded nuclear receptors, mediating transcriptional repression. Ligand-dependent removal of these complexes requires Ubc5-dependent ubiquitylation and proteosomal degradation, with TBLR1 functioning as an essential E3 ligase. Recent studies indicate that NCoR/SMRT complexes are also required for basal repression of NF-κB and AP-1 target genes. Loss of NCoR results in a partially activated phenotype in macrophages. The study found that several inflammatory response genes that are de-repressed in NCoR-deficient macrophages are also subject to transrepression by PPARγ agonists, suggesting a possible role of NCoR in this process. The study focused on the iNOS gene as a model, as it is strongly induced by LPS and negatively regulated by PPARγ agonists. Inhibition of NCoR expression using specific siRNA reversed iNOS transrepression by synthetic ligands. Knockdown of NCoR expression, but not SMRT, reversed iNOS promoter reporter repression by PPARγ in RAW264.7 macrophages. Treatment with a histone deacetylase inhibitor reversed rosiglitazone-dependent transrepression of iNOS. The study also found that HDAC3-specific siRNAs reversed transrepression on the iNOS promoter. These findings suggest that NCoR/HDAC3/TBL complexes associate with the iNOS promoter. Chromatin immunoprecipitation experiments confirmed that NCoR, HDAC3, TBL1, and TBLR1 were present on the iNOS promoter under basal conditions and were cleared following LPS stimulation. However, in cells treated with rosiglitazone or GW0072, both NCoR and HDAC3 remained on the iNA sumoylation-dependent pathway mediates transrepression of inflammatory response genes by PPARγ. PPARγ, a key regulator of adipogenesis and glucose homeostasis, is a target of insulin-sensitizing drugs. While PPARγ agonists are known to suppress inflammatory responses by transrepressing NF-κB target genes, the underlying mechanisms remain unclear. This study identifies a molecular pathway by which PPARγ represses the transcriptional activation of inflammatory genes in macrophages. The process begins with ligand-dependent sumoylation of the PPARγ ligand-binding domain, which targets PPARγ to NCoR/HDAC3 complexes on inflammatory gene promoters. This prevents the recruitment of ubiquitylation/19S proteosome machinery, which normally removes corepressor complexes required for gene activation. As a result, NCoR complexes remain bound to the promoter, maintaining target genes in a repressed state. NCoR and SMRT are components of corepressor complexes containing HDAC3, TBL1, and TBLR1 that interact with unliganded nuclear receptors, mediating transcriptional repression. Ligand-dependent removal of these complexes requires Ubc5-dependent ubiquitylation and proteosomal degradation, with TBLR1 functioning as an essential E3 ligase. Recent studies indicate that NCoR/SMRT complexes are also required for basal repression of NF-κB and AP-1 target genes. Loss of NCoR results in a partially activated phenotype in macrophages. The study found that several inflammatory response genes that are de-repressed in NCoR-deficient macrophages are also subject to transrepression by PPARγ agonists, suggesting a possible role of NCoR in this process. The study focused on the iNOS gene as a model, as it is strongly induced by LPS and negatively regulated by PPARγ agonists. Inhibition of NCoR expression using specific siRNA reversed iNOS transrepression by synthetic ligands. Knockdown of NCoR expression, but not SMRT, reversed iNOS promoter reporter repression by PPARγ in RAW264.7 macrophages. Treatment with a histone deacetylase inhibitor reversed rosiglitazone-dependent transrepression of iNOS. The study also found that HDAC3-specific siRNAs reversed transrepression on the iNOS promoter. These findings suggest that NCoR/HDAC3/TBL complexes associate with the iNOS promoter. Chromatin immunoprecipitation experiments confirmed that NCoR, HDAC3, TBL1, and TBLR1 were present on the iNOS promoter under basal conditions and were cleared following LPS stimulation. However, in cells treated with rosiglitazone or GW0072, both NCoR and HDAC3 remained on the iN