Ovatodiolide alleviates renal fibrosis through regulating metabolic reprogramming via targeting glucose-6-phosphate dehydrogenase

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-06-14 DOI:10.1016/j.phymed.2025.156983

Xiaoyang He , Xiaowen Chen , Wenting Wu , Ruiling Tang , Huiting Wu , Yunyi Liang , Lingyu Shen , Xiaohong Zheng , Zerong Zheng , Ping Yang , Yihao Long , Jinzhu Yang , Liyuan Zhao , Zhe Zhang , Huizhen Wang , Congwei Luo , Fenfen Peng , Haibo Long

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引用次数: 0

Abstract

Background

Ovatodiolide (Ova) is a bioactive compound from Anisomeles indica (l.) Kuntze, which has been traditionally utilized to tonify the kidney function. There is limited targeted therapies available for renal fibrosis (RF) in chronic kidney disease (CKD).

Purpose

This study aims to investigate the effect of Ova on RF and its underlying mechanism.

Methods

Unilateral ischemia-reperfusion injury (UIRI) and unilateral ureteral obstruction (UUO) were intragastrically administrated by solvent (vehicle group) or Ova at two concentations (25 and 50 mg kg⁻¹ day⁻¹) as treatment groups and telmisartan (Tel) as a positive control group. Mass spectrometry (MS), HuProt^TM proteome microarray, surface plasmon resonance (SPR) assays and molecular docking were utilized to explore the molecular mechanism by which Ova regulated metabolic reprogramming in renal tubular epithelial cells (RTECs). In vitro, RTECs were subjected to small interfering RNA (siRNA) and mutant plasmids to evaluate the role of glucose-6-phosphate dehydrogenase (G6PD) in metabolic reprogramming.

Results

Ova treatment markedly attenuated RF in UIRI and UUO mice by suppressing pentose phosphate pathway (PPP) overactivation. Ova bound specifically to G6PD’s Lys403 site, promoted its acetylation and thereby inhibited dimer formation and enzymatic activity without affecting overall protein expression. Notably, Ova effectively inhibited but did not completely abolish G6PD activity, thereby preserving basal PPP levels crucial for cellular survival and physiological functions.

Conclusion

For the first time, we identify Ova as a potential therapeutic agent for RF through selective modulation of G6PD. These findings advance the development of metabolism-targeted therapies for RF, offering scientific and translational value.

Abstract Image

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卵泡二烯内酯通过靶向葡萄糖-6-磷酸脱氢酶调节代谢重编程来减轻肾纤维化

Ova atodiolide （Ova）是一种从茴香中提取的生物活性化合物。中药，传统上被用来补肾。慢性肾脏疾病（CKD）肾纤维化（RF）的靶向治疗有限。目的探讨卵细胞对射频的影响及其机制。方法单侧缺血再灌注损伤（UIRI）和单侧输尿管梗阻（UUO）分别以溶剂（载体组）或卵细胞（25和50 mg kg−1天−1）为治疗组，替米沙坦（Tel）为阳性对照组。利用质谱（MS）、HuProtTM蛋白质组芯片、表面等离子体共振（SPR）和分子对接技术，探讨卵子调控肾小管上皮细胞（RTECs）代谢重编程的分子机制。在体外，研究人员对rtec进行小干扰RNA （siRNA）和突变质粒转染，以评估葡萄糖-6-磷酸脱氢酶（G6PD）在代谢重编程中的作用。结果sova通过抑制戊糖磷酸途径（PPP）的过度激活，显著降低了UIRI和UUO小鼠的RF。卵子特异性结合G6PD的Lys403位点，促进其乙酰化，从而抑制二聚体的形成和酶活性，而不影响整体蛋白的表达。值得注意的是，卵细胞有效抑制但不完全消除G6PD活性，从而保持了对细胞存活和生理功能至关重要的基础PPP水平。结论通过选择性调节G6PD，我们首次发现卵细胞是一种潜在的射频治疗药物。这些发现促进了射频代谢靶向治疗的发展，提供了科学和转化价值。

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

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.