Inhibiting pyruvate carboxylase as a potential therapeutic strategy for alleviating rheumatoid arthritis

Rheumatoid arthritis (RA) is marked by synovial inflammation, cartilage loss, and bone erosion, with macrophages playing a central role. Pyruvate carboxylase (PC), a mitochondrial enzyme, has been linked to inflammation, but its role in RA is unclear.

We investigated the effects of pharmacological PC inhibition with ZY-444 in a collagen antibody-induced arthritis (CAIA) mouse model and assessed disease severity, cytokine production, and histopathology. In vitro, PC expressions were analyzed in U937 cells, macrophages, and LPS-activated macrophages. Functional analysis of PC knockdown was evaluated using qRT-PCR, ELISA, Western blotting, and apoptosis assays.

In CAIA mice, ZY-444 treatment significantly reduced clinical severity, joint inflammation, macrophage infiltration, and histological severity, with efficacy comparable to dexamethasone. ZY-444 suppressed TNF-α and IL-6 in joints and decreased serum IL-6. In vitro, PC expression increased during macrophage differentiation and activation, while PC knockdown markedly reduced cytokine expression and secretion. Mechanistically, PC deficiency attenuated mitogen-activated protein kinase (MAPK) phosphorylation, enhanced macrophage apoptosis, and upregulated HIF-1α expression.

PC regulates macrophage-driven inflammation in RA. Its inhibition alleviates disease pathology, supporting PC as a therapeutic target and ZY-444 as a potential repurposed anti-inflammatory agent.