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Calycosin attenuates renal fibrosis by modulating lipid metabolism via the PCK1/TWIST1/CPT1α axis
Ziyi Qu1, Zhongtang Li1, Yilin Wang1
1Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth clinical Medical College of Guangzhou University of Chinese Medicine, No.1, Fuhua Road, Futian district, Shenzhen, Guangdong, 518033, China.
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 simulations 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.
Insights
Calycosin (CAL) treats chronic kidney disease (CKD) by targeting phosphoenolpyruvate carboxykinase 1 (PCK1). This action corrects kidney lipid metabolism and reduces fibrosis, offering a new therapeutic strategy for CKD.
Area of Science:
- Nephrology
- Pharmacology
- Biochemistry
Background:
- Renal lipid metabolic dysregulation is a key driver of tubular injury and fibrosis in chronic kidney disease (CKD).
- Endogenous targets governing tubular lipid homeostasis in CKD remain incompletely understood.
- Calycosin (CAL), an isoflavone from Astragali Radix, is investigated for its potential therapeutic effects in CKD.
Purpose of the Study:
- To elucidate how calycosin (CAL) corrects renal lipid metabolic dysregulation.
- To determine CAL's role in attenuating fibrosis in chronic kidney disease (CKD).
- To identify endogenous targets of CAL in the kidney.
Main Methods:
- Adenine-induced CKD mouse model and TGF-β1-stimulated HK-2 cells were treated with CAL.
- Lipidomics and network pharmacology identified candidate targets.
- Surface plasmon resonance (SPR), molecular dynamics, and AAV-mediated gene manipulation validated the PCK1/TWIST1/CPT1α axis.
Main Results:
- CAL improved renal function, alleviated fibrosis, and modulated lipid metabolism, reducing harmful lipid accumulation and restoring beneficial lipids.
- CAL directly binds to phosphoenolpyruvate carboxykinase 1 (PCK1).
- CAL activated the PCK1/Twist1/carnitine palmitoyltransferase 1α (CPT1α) axis, enhancing fatty acid oxidation and reducing lipotoxicity.
Conclusions:
- Phosphoenolpyruvate carboxykinase 1 (PCK1) is identified as an endogenous binding target of CAL in the kidney.
- The PCK1/TWIST1/CPT1α axis is the downstream signaling pathway through which CAL corrects tubular lipid disorders and fibrosis.
- This study provides a mechanistic basis for using CAL as a targeted therapy for CKD.
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