Estrogen receptor–autophagy axis protects the heart, aorta and kidneys during perimenopausal aging: Evidence from human cohort and mouse experiments

IF 6.4 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2026-02-15 Epub Date: 2026-01-03 DOI:10.1016/j.lfs.2025.124183

Xiuting Xiang , Weizhou Jiang , Praneetha Palasuberniama , M. Tanveer Hossain Parash , Rahmawati Pare , Yunjun Ruan

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引用次数: 0

Abstract

Aim

The gradual decline in estrogen levels during perimenopause is strongly associated with an increased risk of metabolic and cardiovascular diseases. However, the specific relationship and underlying mechanisms remain incompletely understood. This study combines population data, network pharmacology, and mouse models to explore the detailed mechanisms underlying estrogen's organ-protective effects.

Materials and methods

We utilized data from the National Health and Nutrition Examination Survey (NHANES) to analyze the correlation between estradiol levels and conditions such as hypertension, kidney disease, diabetes, and hypercholesterolemia. A perimenopausal mouse model was established to assess the impact of estrogen replacement therapy on various organs, including the heart, aorta, and kidneys. Network pharmacology was used to identify molecular targets, and receptor-specific inhibitors along with autophagy inhibitors were applied for functional validation in estrogen-treated mice.

Key findings

Lower estradiol levels were significantly associated with an increased risk of hypertension, kidney disease, diabetes, and hypercholesterolemia. Estrogen treatment markedly reduced fibrosis in the heart, aorta, and kidneys, and promoted weight gain in mice, which mirrored BMI trends observed in human cohorts. Network pharmacology identified key molecular targets involved in estradiol-mediated pathways and mTOR-regulated autophagy. Functional validation confirmed that estrogen's protective effects depend on receptor activation and downstream autophagy signaling.

Significance

This study underscores the crucial role of the estrogen receptor-autophagy axis in metabolic regulation and organ protection during perimenopause. It provides new mechanistic insights that could inform precision hormone therapy strategies aimed at preventing aging-related diseases in women.

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雌激素受体自噬轴在围绝经期衰老过程中保护心脏、主动脉和肾脏：来自人类队列和小鼠实验的证据。

目的：围绝经期雌激素水平的逐渐下降与代谢和心血管疾病的风险增加密切相关。然而，具体的关系和潜在的机制仍然不完全清楚。本研究结合人群数据、网络药理学和小鼠模型，探讨雌激素器官保护作用的详细机制。材料和方法：我们利用国家健康和营养调查（NHANES）的数据分析雌二醇水平与高血压、肾病、糖尿病和高胆固醇血症等疾病的相关性。建立围绝经期小鼠模型，评估雌激素替代疗法对不同器官的影响，包括心脏、主动脉和肾脏。网络药理学用于鉴定分子靶点，受体特异性抑制剂和自噬抑制剂应用于雌激素处理小鼠的功能验证。主要发现：较低的雌二醇水平与高血压、肾病、糖尿病和高胆固醇血症的风险增加显著相关。雌激素治疗显著减少了心脏、主动脉和肾脏的纤维化，并促进了小鼠的体重增加，这反映了在人类队列中观察到的BMI趋势。网络药理学确定了参与雌二醇介导途径和mtor调节的自噬的关键分子靶点。功能验证证实雌激素的保护作用依赖于受体激活和下游自噬信号。意义：本研究强调了雌激素受体-自噬轴在围绝经期代谢调节和器官保护中的重要作用。它提供了新的机制见解，可以为旨在预防女性衰老相关疾病的精确激素治疗策略提供信息。

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.