Altered Iron-Mediated Metabolic Homeostasis Governs the Efficacy and Toxicity of Tripterygium Glycosides Tablets Against Rheumatoid Arthritis

IF 10.1 1区 工程技术 Q1 ENGINEERING, MULTIDISCIPLINARY Engineering Pub Date : 2024-08-01 DOI:10.1016/j.eng.2024.04.003
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Abstract

Rheumatoid arthritis (RA), a globally increasing autoimmune disorder, is associated with increased disability rates due to the disruption of iron metabolism. Tripterygium glycoside tablets (TGTs), a Tripterygium wilfordii Hook. f. (TwHF)-based therapy, exhibit satisfactory clinical efficacy for RA treatment. However, drug-induced liver injury (DILI) remains a critical issue that hinders the clinical application of TGTs, and the molecular mechanisms underlying the efficacy and toxicity of TGTs in RA have not been fully elucidated. To address this problem, we integrated clinical multi-omics data associated with the anti-RA efficacy and DILI of TGTs with the chemical and target profiling of TGTs to perform a systematic network analysis. Subsequently, we identified effective and toxic targets following experimental validation in a collagen-induced arthritis (CIA) mouse model. Significantly different transcriptome–protein–metabolite profiles distinguishing patients with favorable TGTs responses from those with poor outcomes were identified. Intriguingly, the clinical efficacy and DILI of TGTs against RA were associated with metabolic homeostasis between iron and bone and between iron and lipids, respectively. Particularly, the signal transducer and activator of transcription 3 (STAT3)–hepcidin (HAMP)/lipocalin 2 (LCN2)–tartrate-resistant acid phosphatase type 5 (ACP5) and STAT3–HAMP–acyl-CoA synthetase long-chain family member 4 (ACSL4)–lysophosphatidylcholine acyltransferase 3 (LPCAT3) axes were identified as key drivers of the efficacy and toxicity of TGTs. TGTs play dual roles in ameliorating CIA-induced pathology and in inducing hepatic dysfunction, disruption of lipid metabolism, and hepatic lipid peroxidation. Notably, TGTs effectively reversed “iron–bone” disruptions in the inflamed joint tissues of CIA mice by inhibiting the STAT3–HAMP/LCN2–ACP5 axis, subsequently leading to “iron–lipid” disturbances in the liver tissues via modulation of the STAT3–HAMP–ACSL4–LPCAT3 axis. Additional bidirectional validation experiments were conducted using MH7A and AML12 cells to confirm the bidirectional regulatory effects of TGTs on key targets. Collectively, our data highlight the association between iron-mediated metabolic homeostasis and the clinical efficacy and toxicity of TGT in RA therapy, offering guidance for the rational clinical use of TwHF-based therapy with dual therapeutic and toxic potential.

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铁介导的新陈代谢平衡改变制约着三尖杉苷片治疗类风湿性关节炎的疗效和毒性
类风湿性关节炎(RA)是一种全球性的自身免疫性疾病,由于铁代谢紊乱而导致致残率增加。三尖杉苷片(TGTs)是一种基于三尖杉(Tripterygium wilfordii Hook. f.,TwHF)的疗法,对治疗类风湿性关节炎具有令人满意的临床疗效。然而,药物性肝损伤(DILI)仍然是阻碍TGTs临床应用的关键问题,而且TGTs在RA中的疗效和毒性的分子机制尚未完全阐明。为了解决这一问题,我们整合了与TGTs抗RA疗效和DILI相关的临床多组学数据以及TGTs的化学和靶点图谱,进行了系统的网络分析。随后,我们在胶原诱导的关节炎(CIA)小鼠模型中进行了实验验证,确定了有效靶点和毒性靶点。我们发现了明显不同的转录组-蛋白质-代谢物图谱,这些图谱将TGTs反应良好的患者与反应不佳的患者区分开来。耐人寻味的是,TGTs 对 RA 的临床疗效和 DILI 分别与铁和骨之间以及铁和脂质之间的代谢平衡有关。特别是,信号转导子和转录激活子3(STAT3)-血钙素(HAMP)/脂钙素2(LCN2)-抗酒石酸磷酸酶5型(ACP5)和STAT3-HAMP-酰基-CoA合成酶长链家族成员4(ACSL4)-赖磷脂酰胆碱酰基转移酶3(LPCAT3)轴被确定为TGTs疗效和毒性的关键驱动因素。TGTs在改善CIA诱导的病理学和诱导肝功能失调、脂质代谢紊乱和肝脏脂质过氧化方面发挥着双重作用。值得注意的是,TGTs通过抑制STAT3-HAMP/LCN2-ACP5轴,有效逆转了CIA小鼠关节炎症组织中的 "铁骨 "紊乱,随后又通过调节STAT3-HAMP-ACSL4-LPCAT3轴,导致肝脏组织中的 "铁脂 "紊乱。我们还利用 MH7A 和 AML12 细胞进行了双向验证实验,以证实 TGTs 对关键靶标的双向调控作用。总之,我们的数据强调了铁介导的代谢平衡与 TGT 在 RA 治疗中的临床疗效和毒性之间的关联,为临床合理使用具有双重治疗和毒性潜力的基于 TwHF 的疗法提供了指导。
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来源期刊
Engineering
Engineering Environmental Science-Environmental Engineering
自引率
1.60%
发文量
335
审稿时长
35 days
期刊介绍: Engineering, an international open-access journal initiated by the Chinese Academy of Engineering (CAE) in 2015, serves as a distinguished platform for disseminating cutting-edge advancements in engineering R&D, sharing major research outputs, and highlighting key achievements worldwide. The journal's objectives encompass reporting progress in engineering science, fostering discussions on hot topics, addressing areas of interest, challenges, and prospects in engineering development, while considering human and environmental well-being and ethics in engineering. It aims to inspire breakthroughs and innovations with profound economic and social significance, propelling them to advanced international standards and transforming them into a new productive force. Ultimately, this endeavor seeks to bring about positive changes globally, benefit humanity, and shape a new future.
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