Jie, L. | Search bioRxiv

bioRxiv2026

PPAR-γ/PCK1 metabolic pathway modulate synovitis and fibrosis in KOA rats

BackgroundKnee osteoarthritis (KOA) is a prevalent degenerative joint disease in which synovial inflammation and fibrosis are closely linked to pain, stiffness, and functional limitation. Growing evidence suggests that metabolic dysregulation, particularly in lipid metabolism, is involved in KOA pathogenesis, but the underlying mechanisms remain incompletely defined. MethodsSprague Dawley rats underwent bilateral anterior cruciate ligament transection to establish a KOA model; sham-operated rats served as controls. RNA sequencing of synovial tissues was performed to identify differentially expressed genes (DEGs) and enriched pathways, followed by GO/KEGG and GSEA analyses. In vivo, adeno-associated virus vectors were used to overexpress or knock down PPAR-{gamma} and phosphoenolpyruvate carboxykinase 1 (PCK1) via intra-articular injection. Ex vivo, primary rat fibroblast-like synoviocytes (FLSs) were stimulated with IL-1{beta} and transfected with PPAR-{gamma} or PCK1 siRNA/overexpression plasmids. synovitis and fibrosis were evaluated by HE, Masson, and Sirius Red staining, immunofluorescence, ELISA, RT-qPCR, and Western blotting. ResultsRNA-seq revealed 621 up-regulated and 228 down-regulated genes in KOA synovium versus sham, with DEGs significantly enriched in PPAR signaling, adipocytokine, and AMPK pathways. Metabolism-related genes including Fabp5, Plin1, Adipoq, Lep, and Pck1 were up-regulated. GSEA indicated downregulation of PPAR-{gamma} signaling in KOA synovium. In vivo and ex vivo, PPAR-{gamma} expression was reduced in KOA, whereas PCK1, FABP5, and ADIPOQ were increased. PPAR-{gamma} overexpression alleviated synovial inflammation, collagen I deposition, and fibrosis, and suppressed FABP5, ADIPOQ, and PCK1 expression; PPAR-{gamma} knockdown produced the opposite effects. Functional studies showed that PCK1 overexpression aggravated synovial inflammatory cell infiltration and fibrosis, elevated IL-1{beta}, IL-18, and TGF-{beta}, and decreased TIMP1 levels in serum, synovial tissue, and FLSs supernatants, whereas PCK1 silencing reversed these changes. ConclusionsThe PPAR-{gamma}/PCK1 metabolic axis modulates synovitis and fibrosis in KOA. Downregulation of PPAR-{gamma} and consequent upregulation of PCK1 promote synovitis and fibrotic remodeling. These findings identify the PPAR-{gamma}/PCK1 pathway as a potential therapeutic target for KOA.

molecular biology↗

bioRxiv2025

Cellular energy sensor SnRK1 suppresses salicylic acid-dependent and -independent defenses and bacterial resistance in Arabidopsis

In nature, plants cope with various pathogens that compete for cellular resources during infection. It has long been suggested that plant defense activity must be linked to cellular energy and metabolic states to optimize the balance between growth and defense. However, the molecular mechanisms that regulate immune activity in relation to cellular energy status remain unclear. Here, we demonstrate that the plant energy sensor SNF1-RELATED KINASE 1 (SnRK1) plays a critical role in modulating defense responses and bacterial resistance in Arabidopsis thaliana. Bacterial elicitor-induced expression of defense marker genes, such as PATHOGENESIS-RELATED 1 (PR1), is significantly repressed under sugar-limited conditions in wild-type seedlings, whereas this expression is markedly enhanced in the snrk1 knockdown mutants. SnRK1 restricts defense-related gene expression and resistance to the biotrophic bacterial pathogen Pseudomonas syringe pv. tomato DC3000, which are partly dependent on salicylic acid (SA). In addition, we found that the SnRK1 kinase activity is increased by high humidity. Consistently, SnRK1 is critical for the suppression of SA-mediated defense responses under high humidity conditions. SnRK1 physically associates with the SA-related transcription factors TGACG SEQUENCE-SPECIFIC BINDING PROTEIN 4 (TGA4) and TGA2 to attenuate PR1 expression. These findings provide valuable insight into the molecular mechanisms linking cellular energy status with immune regulation in plants.

plant biology↗