从“铁-骨/脂”代谢稳态探索雷公藤多苷片治疗类风湿关节炎的“效/毒”关联机制

丁子禾, 王晓月, 张依, 刘健, 万磊, 李涛, 陈凛, 林娜, 张彦琼

工程（英文） ›› 2024, Vol. 39 ›› Issue (8) : 166-179.

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工程（英文） ›› 2024, Vol. 39 ›› Issue (8) : 166-179. DOI: 10.1016/j.eng.2024.04.003
研究论文
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从“铁-骨/脂”代谢稳态探索雷公藤多苷片治疗类风湿关节炎的“效/毒”关联机制

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

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摘要

类风湿关节炎（RA）是一种全球范围内发病率和致残率均不断攀升的自身免疫病。雷公藤多苷片是中药雷公藤（TwHF）的代表性中成药品种，其针对RA的临床疗效确切。值得注意的是，药物性肝损伤（DILI）是限制该品种临床广泛应用的瓶颈问题之一。然而，雷公藤多苷片在治疗RA中的效、毒分子机制均尚未被完全阐明。为了解决这一问题，本研究整合了雷公藤多苷片缓解RA疗效和诱发DILI相关的临床转录组、蛋白质组与代谢组学数据，及其所含化学成分谱和候选靶标谱，开展了多维关联网络分析，不仅识别了其疗效与致毒候选生物标志，还系统解析了其相关分子机制。进一步，采用独立临床样本集，对上述雷公藤多苷片效、毒候选生物标志的临床效能进行验证，并利用胶原诱导性关节炎（CIA）小鼠模型验证其效、毒作用靶标。研究结果表明，雷公藤多苷片缓解RA所发挥的疗效和所诱发的DILI分别与其对“铁-骨”和“铁-脂”代谢稳态的调节密切相关。其中，信号转导和转录激活因子3（STAT3）-肝素（HAMP）/脂质运载蛋白2（LCN2）-抗酒石酸性磷酸酶5型（ACP5）轴所介导的“铁-骨”代谢途径和STAT3-HAMP-长链脂酰辅酶A合成酶4型（ACSL4）-卵磷脂胆碱酰基转移酶3型（LPCAT3）轴所介导的“铁-脂”代谢途径分别是雷公藤多苷片发挥疗效和诱发毒性的关键驱动因素，即，该中成药品种可通过抑制STAT3-HAMP/LCN2-ACP5轴有效逆转了CIA小鼠关节组织中的“铁-骨”紊乱，随后通过调节STAT3-HAMP-ACSL4-LPCAT3轴导致肝脏组织中的“铁-脂”紊乱。进而，在利用MH7A和AML12细胞的体外双向实验验证中，再次确认了雷公藤多苷片对上述关键靶点的双向调控作用。综上，本研究结果证实了“铁-骨/脂”代谢稳态与雷公藤多苷片抗RA疗效和诱发DILI毒性密切关联，为具有“双刃剑”特质中成药品种的临床合理应用提供了新的思路。

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-resis tant 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.

关键词

雷公藤多苷片 / 类风湿关节炎 / 铁代谢 / 临床疗效 / 药物性肝损伤 / 临床多组学分析

Keywords

Tripterygium glycosides tablets / Rheumatoid arthritis / Iron metabolism / Clinical efficacy / Drug-induced liver injury / Clinical multi-omics data analysis

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丁子禾, 王晓月, 张依. 从“铁-骨/脂”代谢稳态探索雷公藤多苷片治疗类风湿关节炎的“效/毒”关联机制. Engineering. 2024, 39(8): 166-179 https://doi.org/10.1016/j.eng.2024.04.003

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