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

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.