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

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外文摘要：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 iden-tified.Intriguingly,the clinical efficacy and DILI of TGTs against RA were associated with metabolic home-ostasis 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 induc-ing 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.

外文关键词：

Tripterygium glycosides tabletsRheumatoid arthritisIron metabolismClinical efficacyDrug-induced liver injuryClinical multi-omics data analysis

作者：

Zihe Ding、Xiaoyue Wang、Yi Zhang、Jian Liu、Lei Wan、Tao Li、Lin Chen、Na Lin、Yanqiong Zhang

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作者单位：

State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs,Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences,Beijing 100700,China

The First Affiliated Hospital of Anhui University of Chinese Medicine,Hefei 230038,China

基金：

Scientific and Technological Innovation Project of the China Academy of Chinese Medical SciencesScientific and Technological Innovation Project of the China Academy of Chinese Medical SciencesNational Natural Science Foundation of ChinaBeijing Municipal Natural Science FoundationInnovation Team and Talents Cultivation Program of National Administration of Traditional Chinese MedicineKey Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine,Institute of Chinese Materia Medica,C

项目编号：

CI2021A03807CI2021A01501823301247212186ZYYCXTD-C-202002

出版年：

2024

DOI：

10.1016/j.eng.2024.04.003

工程(英文)

CSTPCDEI

ISSN：2095-8099

年,卷(期)：2024.39(8)