KLHL20 protects against aldosterone-induced cardiomyocyte cuproptosis by promoting ubiquitination-mediated MR degradation
- 1State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, 250012, China
Abstract
Excessive secretion of mineralocorticoid aldosterone (ALD) and overactivation of mineralocorticoid receptor (MR) are considered major drivers of cardiac remodeling and heart failure in patients with primary aldosteronism. Cuproptosis is a copper-dependent form of regulated cell death that has been implicated in pathological cardiac remodeling. However, its mechanism in ALD/MR-induced cardiac remodeling remains unclear. In this study, it is found that ALD-induced cardiac remodeling is accompanied by copper overload and cuproptosis-associated mitochondrial proteotoxic stress. Kelch like family member 20 (KLHL20) functions as a substrate adaptor of the Cullin3 (CUL3) ubiquitin ligase complex. Its expression is significantly decreased in ALD-stimulated myocardium. Cardiomyocyte-specific knockout of KLHL20 aggravates ALD-induced cuproptosis, myocardial hypertrophy, and interstitial fibrosis. Concurrent treatment with the copper chelator tetrathiomolybdate (TTM) attenuates these aggravated pathological changes. Mechanistically, KLHL20 promotes polyubiquitination and subsequent proteasomal degradation of MR, thereby limiting MR protein accumulation and nuclear localization. Consequently, MR-dependent transcription of the copper transporter Solute carrier family 31 member 1 (SLC31A1) is suppressed. As a result, cardiomyocyte copper overload and mitochondrial proteotoxic stress are alleviated. However, sustained ALD stimulation downregulates KLHL20 expression, thereby weakening KLHL20-mediated control of MR protein stability. Cardiomyocyte-specific overexpression of KLHL20 significantly attenuates cardiac remodeling. These findings indicate that KLHL20 is a clinically viable therapeutic target for combating cardiac remodeling.
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BibTeX
@article{hai2026klhl20,
title = {{KLHL20 protects against aldosterone-induced cardiomyocyte cuproptosis by promoting ubiquitination-mediated MR degradation}},
author = {Jinghan Hai and Huaitao Yu and Yang Hu and Yuan Zhao and Panpan Xu and Xiangping Ma and Xuehui Zheng and Jingyuan Li and Jing Liu and Xiaofan Han and Yun Ti and Peili Bu},
journal = {Redox Biology},
year = {2026},
month = oct,
doi = {10.1016/j.redox.2026.104442},
url = {https://doi.org/10.1016/j.redox.2026.104442},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - KLHL20 protects against aldosterone-induced cardiomyocyte cuproptosis by promoting ubiquitination-mediated MR degradation
AU - Jinghan Hai
AU - Huaitao Yu
AU - Yang Hu
AU - Yuan Zhao
AU - Panpan Xu
AU - Xiangping Ma
AU - Xuehui Zheng
AU - Jingyuan Li
AU - Jing Liu
AU - Xiaofan Han
AU - Yun Ti
AU - Peili Bu
PY - 2026
DA - 2026/10/22
JO - Redox Biology
DO - 10.1016/j.redox.2026.104442
UR - https://doi.org/10.1016/j.redox.2026.104442
AB - Excessive secretion of mineralocorticoid aldosterone (ALD) and overactivation of mineralocorticoid receptor (MR) are considered major drivers of cardiac remodeling and heart failure in patients with primary aldosteronism. Cuproptosis is a copper-dependent form of regulated cell death that has been implicated in pathological cardiac remodeling. However, its mechanism in ALD/MR-induced cardiac remodeling remains unclear. In this study, it is found that ALD-induced cardiac remodeling is accompanied by copper overload and cuproptosis-associated mitochondrial proteotoxic stress. Kelch like family member 20 (KLHL20) functions as a substrate adaptor of the Cullin3 (CUL3) ubiquitin ligase complex. Its expression is significantly decreased in ALD-stimulated myocardium. Cardiomyocyte-specific knockout of KLHL20 aggravates ALD-induced cuproptosis, myocardial hypertrophy, and interstitial fibrosis. Concurrent treatment with the copper chelator tetrathiomolybdate (TTM) attenuates these aggravated pathological changes. Mechanistically, KLHL20 promotes polyubiquitination and subsequent proteasomal degradation of MR, thereby limiting MR protein accumulation and nuclear localization. Consequently, MR-dependent transcription of the copper transporter Solute carrier family 31 member 1 (SLC31A1) is suppressed. As a result, cardiomyocyte copper overload and mitochondrial proteotoxic stress are alleviated. However, sustained ALD stimulation downregulates KLHL20 expression, thereby weakening KLHL20-mediated control of MR protein stability. Cardiomyocyte-specific overexpression of KLHL20 significantly attenuates cardiac remodeling. These findings indicate that KLHL20 is a clinically viable therapeutic target for combating cardiac remodeling.
SN - 2213-2317
ER -