Calycosin attenuates renal fibrosis by modulating lipid metabolism via the PCK1/TWIST1/CPT1α axis.

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2026-04-30 DOI:10.1016/j.lfs.2026.124423

Ziyi Qu, Zhongtang Li, Yilin Wang, Beibei Jiang, Jiahui Liu, Riming He, Shudong Yang

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引用次数: 0

Abstract

Aims: Renal lipid metabolic dysregulation drives tubular injury and fibrosis in chronic kidney disease (CKD), yet endogenous targets governing tubular lipid homeostasis remain incompletely understood. This study aimed to elucidate how calycosin (CAL), an O-methylated isoflavone from Astragali Radix, corrects renal lipid metabolic dysregulation and attenuates fibrosis in CKD.

Materials and methods: An adenine-induced CKD mouse model and TGF-β1-stimulated HK-2 cells were treated with CAL. Lipidomics and network pharmacology screened candidate targets. Surface plasmon resonance (SPR) and molecular dynamics simulation validated target binding. Adeno-associated virus (AAV)-mediated renal phosphoenolpyruvate carboxykinase 1 (PCK1) overexpression in vivo and lentiviral overexpression in vitro established the regulatory relationship. The PCK1 inhibitor 3-mercaptopicolinic acid served as reverse validation.

Key findings: CAL improved renal function, alleviated fibrosis, and reduced lipid deposition both in vivo and in vitro. Lipidomics revealed that CAL bidirectionally modulated renal lipid metabolism by suppressing glycerophospholipid, sphingolipid, and glycerolipid accumulation while restoring omega-3 PUFA-enriched lipids and decreasing lipid saturation. SPR confirmed direct binding of CAL to PCK1. Gain-of-function experiments demonstrated that PCK1 negatively regulates Twist family BHLH transcription factor 1 (TWIST1) in the kidney. Accordingly, CAL activated the PCK1/TWIST1/carnitine palmitoyltransferase 1 A (CPT1α) axis, restoring fatty acid oxidation and suppressing lipid uptake, thereby attenuating lipotoxicity-driven oxidative stress and tubular apoptosis.

Significance: This study identifies PCK1 as an endogenous binding target of CAL in the kidney and delineates the PCK1/TWIST1/CPT1α axis as the downstream signaling circuitry through which CAL corrects tubular lipid metabolic disorders and attenuates renal fibrosis, providing mechanistic rationale for targeted CKD therapy.

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毛蕊异黄酮通过PCK1/TWIST1/CPT1α轴调节脂质代谢减轻肾纤维化。

目的：慢性肾脏疾病（CKD）的肾脂代谢失调驱动小管损伤和纤维化，但控制小管脂质稳态的内源性靶标仍不完全清楚。本研究旨在阐明来自黄芪的o -甲基化异黄酮calycosin （CAL）如何纠正肾脏脂质代谢失调并减轻CKD中的纤维化。材料和方法：用CAL处理腺嘌呤诱导的CKD小鼠模型和TGF-β1刺激的HK-2细胞，脂质组学和网络药理学筛选候选靶点。表面等离子体共振（SPR）和分子动力学模拟验证了靶结合。腺相关病毒（AAV）介导的肾磷酸烯醇丙酮酸羧激酶1 （PCK1）在体内过表达与慢病毒在体外过表达建立了调控关系。PCK1抑制剂3-巯基氨基甲酸进行反向验证。主要发现：CAL在体内和体外均可改善肾功能，减轻纤维化，减少脂质沉积。脂质组学显示，CAL通过抑制甘油磷脂、鞘脂和甘油脂积累，同时恢复富含omega-3 pufa的脂质，降低脂质饱和度，双向调节肾脏脂质代谢。SPR证实CAL与PCK1直接结合。功能增益实验表明PCK1负调控肾脏Twist家族BHLH转录因子1 （TWIST1）。因此，CAL激活PCK1/TWIST1/肉碱棕榈酰基转移酶1 A （CPT1α）轴，恢复脂肪酸氧化，抑制脂质摄取，从而减轻脂毒性驱动的氧化应激和小管凋亡。意义：本研究确定PCK1是肾脏中CAL的内源性结合靶点，并描述PCK1/TWIST1/CPT1α轴是CAL纠正小管脂质代谢紊乱和减轻肾纤维化的下游信号通路，为靶向CKD治疗提供了机制基础。

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

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.