Uncovering the Efficacy and Mechanism of Zhenwu Decoction for Hypothyroidism Based on Non-Targeted Metabolomics.

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2025-06-25 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S527163

Yuhan Wang, Yancun Li, Mengyao Tang, Luhan Zhang, Shu Zhu

{"title":"Uncovering the Efficacy and Mechanism of Zhenwu Decoction for Hypothyroidism Based on Non-Targeted Metabolomics.","authors":"Yuhan Wang, Yancun Li, Mengyao Tang, Luhan Zhang, Shu Zhu","doi":"10.2147/DDDT.S527163","DOIUrl":null,"url":null,"abstract":"Background: Hypothyroidism, a systemic hypometabolic syndrome from deficient thyroid hormone synthesis/utilization, has high prevalence and complex mechanisms. Levothyroxine-based lifelong therapy risks neurocognitive/metabolic complications and iatrogenic pathologies (eg, osteoporosis, hepatocardiac dysfunction). Zhenwu Decoction (ZW), a classical multi-target herbal formulation, shows therapeutic potential but requires mechanistic clarity on thyroid restoration to enable standardized translation.Objective: To investigate ZW's therapeutic mechanisms in hypothyroidism via serum metabolomics and pathway analysis.Methods: Twenty-seven Wistar rats were randomly divided into three groups: control group (n=9), PTU model group (n=9), and Zhenwu Tang group (n=9). The hypothyroidism rat model was induced by administering propylthiouracil (PTU) by gastric gavage for 4 weeks in the PTU model and Zhenwu Tang groups, while the control group received no treatment. Subsequently, the Zhenwu Tang group underwent a 3-week herbal medicine intervention. Multidimensional validation (including phenotypic monitoring, ELISA for FT4/TSH, and HE staining) was performed to confirm the successful establishment of the model and to evaluate the therapeutic efficacy of Zhenwu Tang (ZW). Untargeted UPLC-MS/MS metabolomics was performed to identify differential metabolites (VIP >1, p <0.05), and MetaboAnalyst 5.0 was used to map key pathways.Results: ZW can significantly improve systemic indicators (body weight, anal temperature, feeding behavior) in hypothyroid rats. It remarkably improves the histopathological features of the thyroid gland, approaching the structure of the normal group. In addition, ZW can significantly regulate serum thyroid hormone levels (decrease TSH and increase FT4), approaching normal levels.47 metabolites (eg, L-proline, fumaric acid, estradiol) and 7 pathways (thermogenesis, cholesterol metabolism) were identified. ZW corrected metabolic dysfunction through multi-target regulation.Conclusion: ZW exerts therapeutic effects by modulating glucose-6-phosphate, bile acids, and critical metabolic pathways, thereby advancing our understanding of hypothyroidism pathophysiology and underscoring its potential for clinical translation and therapeutic development.","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"5431-5451"},"PeriodicalIF":4.7000,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12206430/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Design, Development and Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2147/DDDT.S527163","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Background: Hypothyroidism, a systemic hypometabolic syndrome from deficient thyroid hormone synthesis/utilization, has high prevalence and complex mechanisms. Levothyroxine-based lifelong therapy risks neurocognitive/metabolic complications and iatrogenic pathologies (eg, osteoporosis, hepatocardiac dysfunction). Zhenwu Decoction (ZW), a classical multi-target herbal formulation, shows therapeutic potential but requires mechanistic clarity on thyroid restoration to enable standardized translation.

Objective: To investigate ZW's therapeutic mechanisms in hypothyroidism via serum metabolomics and pathway analysis.

Methods: Twenty-seven Wistar rats were randomly divided into three groups: control group (n=9), PTU model group (n=9), and Zhenwu Tang group (n=9). The hypothyroidism rat model was induced by administering propylthiouracil (PTU) by gastric gavage for 4 weeks in the PTU model and Zhenwu Tang groups, while the control group received no treatment. Subsequently, the Zhenwu Tang group underwent a 3-week herbal medicine intervention. Multidimensional validation (including phenotypic monitoring, ELISA for FT4/TSH, and HE staining) was performed to confirm the successful establishment of the model and to evaluate the therapeutic efficacy of Zhenwu Tang (ZW). Untargeted UPLC-MS/MS metabolomics was performed to identify differential metabolites (VIP >1, p <0.05), and MetaboAnalyst 5.0 was used to map key pathways.

Results: ZW can significantly improve systemic indicators (body weight, anal temperature, feeding behavior) in hypothyroid rats. It remarkably improves the histopathological features of the thyroid gland, approaching the structure of the normal group. In addition, ZW can significantly regulate serum thyroid hormone levels (decrease TSH and increase FT4), approaching normal levels.47 metabolites (eg, L-proline, fumaric acid, estradiol) and 7 pathways (thermogenesis, cholesterol metabolism) were identified. ZW corrected metabolic dysfunction through multi-target regulation.

Conclusion: ZW exerts therapeutic effects by modulating glucose-6-phosphate, bile acids, and critical metabolic pathways, thereby advancing our understanding of hypothyroidism pathophysiology and underscoring its potential for clinical translation and therapeutic development.

查看原文本刊更多论文

基于非靶向代谢组学揭示真五汤治疗甲状腺功能减退的疗效及机制。

背景：甲状腺功能减退症是一种由甲状腺激素合成/利用不足引起的全身性低代谢综合征，发病率高，机制复杂。以左甲状腺素为基础的终身治疗存在神经认知/代谢并发症和医源性病理（如骨质疏松症、肝功能障碍）的风险。真武汤是一种经典的多靶点中药制剂，显示出治疗潜力，但需要明确甲状腺恢复的机制，以便标准化翻译。目的：通过血清代谢组学和途径分析，探讨中西医结合治疗甲状腺功能减退的作用机制。方法：将27只Wistar大鼠随机分为3组：对照组（n=9）、PTU模型组（n=9）、真武汤组（n=9）。PTU模型组和真物汤组灌胃给予丙硫脲嘧啶（PTU） 4周，建立甲状腺功能减退大鼠模型，对照组不给药。随后，真五汤组进行为期3周的中药干预。多维度验证（包括表型监测、ELISA检测FT4/TSH、HE染色）证实模型建立成功，评价真武汤（ZW）的治疗效果。采用非靶向UPLC-MS/MS代谢组学方法鉴定差异代谢物（VIP >1, p）。结果：ZW能显著改善甲状腺功能减退大鼠的全身指标（体重、肛门温度、摄食行为）。显著改善甲状腺组织病理学特征，接近正常组的结构。此外，ZW能显著调节血清甲状腺激素水平（降低TSH，增加FT4），接近正常水平。鉴定出47种代谢物（如l -脯氨酸、富马酸、雌二醇）和7种途径（产热、胆固醇代谢）。ZW通过多靶点调控纠正代谢功能障碍。结论：ZW通过调节葡萄糖-6-磷酸、胆汁酸和关键代谢途径发挥治疗作用，从而促进了我们对甲状腺功能减退症病理生理的理解，并强调了其临床转化和治疗开发的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.