Calycosin alleviates myocardial injury in diabetic mice by enhancing lipophagy in cardiomyocytes via Rab7a regulation
- 1College of Pharmacy, Qiqihar Medical University
- 2Heilongjiang University of Chinese Medicine
Abstract
Background: Diabetic cardiomyopathy (DCM) is a major life-threatening cardiovascular complication of diabetes mellitus, characterized by myocardial lipid deposition, lipotoxicity and progressive cardiac dysfunction. Impaired lipophagy—the selective autophagic clearance of lipid droplets (LDs)—is a key driver of DCM progression, and Rab7a, a small GTPase, is essential for autophagosome–lysosome fusion, the rate-limiting step of efficient lipophagic degradation. Calycosin (CA), a natural isoflavone derived from Astragalus membranaceus , exerts antidiabetic and cardioprotective effects. However, whether CA regulates lipophagy via Ras-related protein Rab-7a (Rab7a) to ameliorate DCM remains largely unknown. The present study investigated whether CA alleviates DCM by promoting lipophagy through Rab7a-dependent mechanisms.
Methods: In vivo , DCM was induced in male C57BL/6J mice by a high-fat diet combined with low-dose streptozotocin (STZ), followed by daily CA administration. In vitro , neonatal mouse cardiomyocytes (NMCMs) were isolated and exposed to high glucose and high lipid (HGHL) conditions to mimic the DCM microenvironment. Cardiac function was assessed by echocardiography. Myocardial lipid accumulation was evaluated by Oi-Red O staining, Bodipy staining and triglyceride (TG) quantification assay. Lipophagy was monitored using transmission electron microscopy (TEM), LC3-LD colocalization analysis and Western blotting. Rab7a was knocked down in NMCMs using specific small interfering RNAs (siRNAs), and its ubiquitination level was detected by co-immunoprecipitation (Co-IP) assay.
Results: CA significantly improved cardiac function, reduced myocardial fibrosis and lipid accumulation, and restored impaired lipophagic flux in DCM mice. Consistently, in HGHL-stimulated NMCMs, CA promoted lipophagy and suppressed lipotoxic injury. Mechanistically, CA upregulated Rab7a protein expression and inhibited its ubiquitination. Rab7a knockdown abolished CA-mediated lipophagy activation and subsequent lipid clearance.
Conclusion: CA enhances cardiomyocyte lipophagy by upregulating Rab7a and suppressing its ubiquitination, thereby mitigating excessive lipid deposition and subsequent myocardial injury in DCM mice. These findings reveal a novel mechanism by which CA regulates cardiomyocyte lipophagy and highlight Rab7a-mediated lipophagy as a promising therapeutic target for diabetic cardiac lipotoxicity.
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BibTeX
@article{zhang2026calycosin,
title = {{Calycosin alleviates myocardial injury in diabetic mice by enhancing lipophagy in cardiomyocytes via Rab7a regulation}},
author = {Qi Zhang and Mingyu Li and Xiaowan Zhao and Yuchun Wang and Yiwen Jiang and Yu Feng and Ming Wang and Honglian Zhang and Pengling Ge and Jianwen Zhou and Jicheng Liu},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1880993},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1880993/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Calycosin alleviates myocardial injury in diabetic mice by enhancing lipophagy in cardiomyocytes via Rab7a regulation
AU - Qi Zhang
AU - Mingyu Li
AU - Xiaowan Zhao
AU - Yuchun Wang
AU - Yiwen Jiang
AU - Yu Feng
AU - Ming Wang
AU - Honglian Zhang
AU - Pengling Ge
AU - Jianwen Zhou
AU - Jicheng Liu
PY - 2026
DA - 2026/10/22
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1880993
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1880993/full
AB - Background: Diabetic cardiomyopathy (DCM) is a major life-threatening cardiovascular complication of diabetes mellitus, characterized by myocardial lipid deposition, lipotoxicity and progressive cardiac dysfunction. Impaired lipophagy—the selective autophagic clearance of lipid droplets (LDs)—is a key driver of DCM progression, and Rab7a, a small GTPase, is essential for autophagosome–lysosome fusion, the rate-limiting step of efficient lipophagic degradation. Calycosin (CA), a natural isoflavone derived from Astragalus membranaceus , exerts antidiabetic and cardioprotective effects. However, whether CA regulates lipophagy via Ras-related protein Rab-7a (Rab7a) to ameliorate DCM remains largely unknown. The present study investigated whether CA alleviates DCM by promoting lipophagy through Rab7a-dependent mechanisms. Methods: In vivo , DCM was induced in male C57BL/6J mice by a high-fat diet combined with low-dose streptozotocin (STZ), followed by daily CA administration. In vitro , neonatal mouse cardiomyocytes (NMCMs) were isolated and exposed to high glucose and high lipid (HGHL) conditions to mimic the DCM microenvironment. Cardiac function was assessed by echocardiography. Myocardial lipid accumulation was evaluated by Oi-Red O staining, Bodipy staining and triglyceride (TG) quantification assay. Lipophagy was monitored using transmission electron microscopy (TEM), LC3-LD colocalization analysis and Western blotting. Rab7a was knocked down in NMCMs using specific small interfering RNAs (siRNAs), and its ubiquitination level was detected by co-immunoprecipitation (Co-IP) assay. Results: CA significantly improved cardiac function, reduced myocardial fibrosis and lipid accumulation, and restored impaired lipophagic flux in DCM mice. Consistently, in HGHL-stimulated NMCMs, CA promoted lipophagy and suppressed lipotoxic injury. Mechanistically, CA upregulated Rab7a protein expression and inhibited its ubiquitination. Rab7a knockdown abolished CA-mediated lipophagy activation and subsequent lipid clearance. Conclusion: CA enhances cardiomyocyte lipophagy by upregulating Rab7a and suppressing its ubiquitination, thereby mitigating excessive lipid deposition and subsequent myocardial injury in DCM mice. These findings reveal a novel mechanism by which CA regulates cardiomyocyte lipophagy and highlight Rab7a-mediated lipophagy as a promising therapeutic target for diabetic cardiac lipotoxicity.
SN - 1663-9812
ER -