Disruption of Treg Homeostasis in Rheumatoid Arthritis via Ferroptosis-Mediated ETC Collapse and TXK-STAT3/PLCγ1 Activation - PubMed
2 hours ago
- #Regulatory T Cells
- #Ferroptosis
- #Rheumatoid Arthritis
- Synovial iron overload in rheumatoid arthritis (RA) creates a ferroptosis-permissive microenvironment, disrupting regulatory T cell (Treg) homeostasis.
- RA synovial fluid induces ferroptosis in Tregs, leading to lipid peroxide-driven mitochondrial dysfunction, electron transport chain (ETC) collapse, and impaired oxidative phosphorylation (OXPHOS).
- Ferroptotic stress triggers TXK kinase upregulation, which phosphorylates STAT3 and PLCγ1, activating a proinflammatory program that destabilizes Treg identity and promotes Th17-like conversion.
- Iron chelation or TXK inhibition reverses this pathogenic reprogramming both in vitro and in vivo, restoring Treg functionality.
- The study identifies a ferroptosis-ETC-TXK/STAT3 axis as a core mechanism of synovial Treg failure, suggesting therapeutic strategies targeting synovial iron homeostasis or TXK signaling to restore immune tolerance in RA.