Fn14 signalling participates in pristane‐induced murine lupus through exacerbating oxidative stress

Background and Purpose Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by oxidative stress and immune dysregulation. Fibroblast growth factor‐inducible 14 (Fn14) has been implicated in tissue injury, but its specific role in SLE pathogenesis remains unclear. This study investigates whether Fn14 modulates disease severity by driving oxidative stress and the subsequent imbalance of Th17/Treg cells. Experimental Approach Lupus was induced in both wild‐type and Fn14 knockout mice via pristane administration. Disease severity was evaluated through lupus nephritis, skin lesions and arthritis, along with oxidative stress markers. Proteomic analysis of kidney tissue identified dysregulated redox‐regulatory proteins. In vitro , TWEAK‐pretreated mouse glomerular mesangial cells were assessed for Fn14‐mediated oxidative responses. Flow cytometry quantified the impact of Fn14 on the balance of Th17 and Treg cells. Key Results Fn14‐deficient mice exhibited significantly reduced lupus severity across all affected organs. This protection was accompanied by decreased oxidative stress markers and increased NRF2 levels. Proteomic analysis confirmed that Fn14 deficiency reversed the dysregulation of multiple redox‐regulatory proteins in kidney tissue. In vitro , TWEAK pretreatment sensitized mesangial cells to oxidative challenge, potentiating reactive oxygen species (ROS) generation while simultaneously suppressing antioxidant defences. Furthermore, Fn14 deficiency corrected the Th17/Treg imbalance associated with oxidative stress. Conclusion and Implications Fn14 deficiency alleviates lupus severity by mitigating oxidative stress and correcting the Th17/Treg imbalance. The TWEAK/Fn14 axis promotes oxidative injury by priming target cells for exaggerated pro‐oxidant responses while compromising antioxidant systems. These results highlight the therapeutic potential of targeting Fn14 to counteract oxidative stress and immune dysregulation in SLE.