PPAR-γ dysregulation links NF-κB activation and Nrf2-driven antioxidant responses in axial spondyloarthritis: A pilot study

Background: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease primarily affecting the axial skeleton. Expression studies support a role for inflammatory and immunomodulatory pathways in disease onset and progression. In this context, peroxisome proliferator-activated receptor (PPAR)-γ has been implicated in axSpA and is known to inhibit nuclear factor kappa B (NF-κB) and its related inflammatory signaling. Methods: We characterized PPAR-γ deficit and related antioxidant and inflammatory response in axSpA patients, compared to healthy subjects, through the analysis of peripheral blood mononuclear cells (PBMCs). Real time PCR was employed to measure PPAR genes in PBMCs from healthy and axSpA subjects, while antioxidant, inflammatory, and apoptotic markers were assessed using a targeted RNAseq (AmpliSeq) panel. Exploratory correlations between molecular alterations and disease activity were evaluated using Matlab R2021b. Functional enrichment analysis was performed by using g:Profiler. PBMC immunophenotyping was performed through flow cytometry, while lipid-derived signaling molecules were quantified by ELISA. Results: PPAR-γ expression was significantly reduced in PBMCs from axSpA patients and was paralleled by the upregulation of several genes related to oxidative stress response, inflammation and apoptosis, as well as by increased serum prostaglandin PGJ2 levels and differences in blood parameter correlation profiles compared with healthy subjects. These molecular alterations were also associated with a significant increase in CD11b-positive cells. Functional enrichment analysis within the axSpA cohort confirmed the involvement of antioxidant activity together with cytokine receptor binding, cellular response to chemical stimuli, and regulation of molecular function clusters. Exploratory correlation analyses with ASDAS-CRP revealed heterogeneous directional patterns across dysregulated genes, with IL1RN showing the clearest positive association with disease activity and IFNG displaying an inverse trend. Heterogeneous directional patterns were also observed across PPAR isoforms. Conclusions: Overall, these findings support an association between reduced PPAR-γ expression, NF-κB signaling pathway activation, and Nrf2-related antioxidant response in axSpA, laying the groundwork for a better understanding of the immune molecular landscape of the disease. These results may contribute to the identification of PBMC-based molecular signatures that, after validation in larger cohorts, could support future personalized therapeutic strategies.