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

IF 9.9 1区医学 Q1 RHEUMATOLOGY

Arthritis & Rheumatology Pub Date : 2026-08-25 Epub Date: 2026-04-21 DOI:10.1002/art.70110

Yale Liu MD, PhD, Zhu Yan MD, Xueting Peng MD, Meixuan Li MD, Juan Wang MD, PhD, Yan Zhang PhD, Xiaoqian Hu MD, Mingzhu Zhou MD, Kaixuan Ren MD, Dan Zhang PhD, Xingyi Guo PhD, Yumin Xia MD, PhD, Huanhuan Huo MD

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引用次数: 0

Abstract

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.

Abstract Image

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TWEAK/Fn14信号驱动系统性红斑狼疮的氧化性心脏损伤：来自患者生物标志物研究、狼疮小鼠模型和心肌细胞分析的证据

目的：心脏受累是系统性红斑狼疮（SLE）发病的主要原因。肿瘤坏死因子样细胞凋亡弱诱导剂（TWEAK）在SLE中升高，但其在狼疮相关心脏损伤中的作用尚不清楚。我们研究了TWEAK/Fn14信号在sle相关心肌病中的作用及其作为生物标志物和治疗靶点的潜力。方法：对242例SLE患者和66例年龄和性别匹配的对照组进行血清TWEAK、炎症细胞因子、自身抗体和氧化应激标志物的检测，并与超声心动图、心电图和心肌酶结果进行相关性分析。采用组织病理学、免疫印迹、免疫荧光和定量蛋白质组学方法，对野生型和fn14缺陷小鼠的pristane诱导狼疮模型的心脏病理和氧化还原信号进行了评估。在狼疮易感MRL/lpr小鼠分离的原代心肌细胞中，研究了TWEAK对线粒体氧化应激、抗氧化信号和细胞凋亡的直接影响。结果：SLE患者血清TWEAK水平显著升高，与健康对照相比，心脏异常患者血清TWEAK水平最高。TWEAK与丙二醛、8-羟基-2′-脱氧鸟苷、疾病活动性和炎症细胞因子呈正相关，与超氧化物歧化酶呈负相关。升高的基线TWEAK预测了随访期间新的心脏异常，并随着临床改善而下降。在狼疮小鼠中，Fn14缺乏减少了心脏活性氧的积累，恢复了Nrf2/HO-1抗氧化信号，减轻了组织病理损伤，并保留了心功能。在体外，TWEAK诱导狼疮易感心肌细胞产生线粒体超氧化物，抑制Nrf2信号，促进细胞凋亡。结论：TWEAK/Fn14信号驱动SLE中氧化应激介导的心肌细胞损伤，是狼疮相关心脏损伤的一个有希望的生物标志物和治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Arthritis & Rheumatology RHEUMATOLOGY-

CiteScore

20.90

自引率

3.00%

发文量

371

期刊介绍： Arthritis & Rheumatology is the official journal of the American College of Rheumatology and focuses on the natural history, pathophysiology, treatment, and outcome of rheumatic diseases. It is a peer-reviewed publication that aims to provide the highest quality basic and clinical research in this field. The journal covers a wide range of investigative areas and also includes review articles, editorials, and educational material for researchers and clinicians. Being recognized as a leading research journal in rheumatology, Arthritis & Rheumatology serves the global community of rheumatology investigators and clinicians.