TWEAK /Fn14 Signaling Drives Oxidative Cardiac Injury in Systemic Lupus Erythematosus: Evidence From Patient Biomarker Studies, Lupus Mouse Models, and Cardiomyocyte Assays

OBJECTIVE: Cardiac involvement is a major cause of morbidity in systemic lupus erythematosus (SLE). Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is elevated in SLE, but its contribution to lupus-associated cardiac injury is unclear. We investigated the role of TWEAK/fibroblast growth factor-inducible 14 (Fn14) signaling in SLE-related cardiomyopathy and its potential as a biomarker and therapeutic target. METHODS: Serum TWEAK, inflammatory cytokines, autoantibodies, and oxidative stress markers were measured in 242 patients with SLE and 66 age- and sex-matched controls, with correlation to echocardiographic, electrocardiographic, and myocardial enzyme findings. Cardiac pathology and redox signaling were assessed in pristane-induced lupus models using wild-type mice and mice deficient of Fn14 by histopathology, immunoblotting, immunofluorescence, and quantitative proteomics. Direct effects of TWEAK on mitochondrial oxidative stress, antioxidant signaling, and apoptosis were examined in primary cardiomyocytes isolated from MRL/lpr mice who were lupus prone. RESULTS: Serum TWEAK levels were significantly elevated in patients with SLE and were highest in those with cardiac abnormalities compared with healthy controls. TWEAK correlated positively with malondialdehyde, 8-hydroxy-2'-deoxyguanosine, disease activity, and inflammatory cytokines and inversely with superoxide dismutase. Elevated baseline TWEAK predicted new cardiac abnormalities during follow-up and declined with clinical improvement. In mice with lupus, Fn14 deficiency reduced cardiac reactive oxygen species accumulation, restored Nrf2/HO-1 antioxidant signaling, attenuated histopathological injury, and preserved cardiac function. In vitro, TWEAK induced mitochondrial superoxide production, suppressed Nrf2 signaling, and promoted apoptosis in lupus-prone cardiomyocytes. CONCLUSION: TWEAK/Fn14 signaling drives oxidative stress-mediated cardiomyocyte injury in SLE and represents a promising biomarker and therapeutic target for lupus-associated cardiac damage.