Disruption of Treg Homeostasis in Rheumatoid Arthritis via Ferroptosis-Mediated ETC Collapse and TXK-STAT3/PLCγ1 Activation.

In rheumatoid arthritis (RA), regulatory T cells (Tregs) within the synovium present a paradox: they are numerically enriched yet functionally impaired, leading to a loss of immune tolerance. Here, we report that synovial iron overload establishes a ferroptosis-permissive microenvironment that disrupts Treg homeostasis. Exposure to RA synovial fluid induced ferroptosis, autoimmune Treg-associated metabolic shifts through lipid peroxide-driven mitochondrial dysfunction, characterized by electron transport chain (ETC) collapse and impaired oxidative phosphorylation. Mechanistically, metabolic disturbance by ferroptotic stress or complex III blockade triggered TXK kinase upregulation, which is required for the phosphorylation of STAT3 (Tyr705) and PLCγ1 (Tyr783), activating a proinflammatory transcriptional program that destabilized Treg identity and promoted Th17-like conversion. Crucially, this pathogenic reprogramming was reversed through iron chelation or TXK inhibition in vitro and in vivo. Our findings unveil a ferroptosis-ETC-TXK/STAT3 axis as a core mechanism of synovial Treg failure. Targeting synovial iron homeostasis or inhibiting TXK signaling thus represents a promising therapeutic strategy to restore immune tolerance in RA by rescuing Treg functionality.