The Estrogen–Autophagy Axis: Insights into Cytoprotection and Therapeutic Potential in Cancer and Infection

Sep 21, 2026

Macroautophagy serves as an essential cytoprotective mechanism for cellular homeostasis and is increasingly targeted for therapies against cancers and infectious diseases. Debate remains over whether autophagy should be inhibited or stimulated in complex disease settings. Estrogen is presented as a major source of variability through its correlations with autophagy signaling. This review compiles molecular mechanisms and recent ligand- and context-specific findings, highlights regulators of autophagy under estrogen influence, and proposes a model linking the estrogen–autophagy axis to cell fate decisions.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages20

Reading Time50 min

AccessFree to download

Introduction

Estrogen receptors and proposed autophagy modulation

Estrogen effects on cancer cell growth and autophagy regulation

Estrogen–autophagy crosstalk in immunity and disease

Review The Estrogen–Autophagy Axis: Insights into Cytoprotection and Therapeutic Potential in Cancer and Infection Ying Zhao 1, Daniel J. Klionsky 2, Xin Wang 1, Qiaoying Huang 1, Zixin Deng 1 and Jin Xiang 1, * Citation: Zhao, Y.; Klionsky, D.J.; Wang, X.; Huang, Q.; Deng, Z.; Xiang, J. The Estrogen–Autophagy Axis: Insights into Cytoprotection and Therapeutic Potential in Cancer and Infection. Int. J. Mol. Sci. 2024, 25, 12576. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms252312576 Academic Editor: Matin Sheriff Received: 23 October 2024 Revised: 14 November 2024 Accepted: 16 November 2024 Published: 22 November 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China; [zying1305@163.com](zying1305@163.com) (Y.Z.); [w919074903@163.com](w919074903@163.com) (X.W.); [2021313061063@whu.edu.cn](2021313061063@whu.edu.cn) (Q.H.); [zxdeng@sjtu.edu.cn](zxdeng@sjtu.edu.cn) (Z.D.) 2 Life Sciences Institute, University of Michigan, Mary Sue Coleman Hall, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA; [klionsky@umich.edu](klionsky@umich.edu) * Correspondence: [xiangjin@whu.edu.cn](xiangjin@whu.edu.cn) Abstract: Macroautophagy, commonly referred to as autophagy, is an essential cytoprotective mechanism that plays a significant role in cellular homeostasis. It has emerged as a promising target for drug development aimed at treating various cancers and infectious diseases. However, the scientific community has yet to reach a consensus on the most effective approach to manipulating autophagy, with ongoing debates about whether its inhibition or stimulation is preferable for managing these complex conditions. One critical factor contributing to the variability in treatment responses for both cancers and infectious diseases is estrogen, a hormone known for its diverse biological effects. Given the strong correlations observed between estrogen signaling and autophagy, this review seeks to summarize the intricate molecular mechanisms that underlie the dual cytoprotective effects of estrogen signaling in conjunction with autophagy. We highlight recent findings from studies that involve various ligands, disease contexts, and cell types, including immune cells. Furthermore, we discuss several factors that regulate autophagy in the context of estrogen’s influence. Ultimately, we propose a hypothetical model to elucidate the regulatory effects of the estrogen–autophagy axis on cell fate. Understanding these interactions is crucial for advancing our knowledge of related diseases and facilitating the development of innovative treatment strategies. Keywords: autophagy; cancer; estrogen; immunity; infection 1. Introduction Autophagy is a crucial cytoprotective response that helps cells cope with pathological stresses associated with various diseases, including cancer, ischemia, and infections. It plays a vital role in maintaining the intracellular balance of mass and energy necessary for metabolism, growth, development, and immune function. However, while autophagy is protective in healthy cells, it can also promote drug resistance and nutrient deficiency in cancer cells [1,2] . This dual nature makes autophagy an appealing therapeutic target, as it is intricately linked to a range of metabolic diseases, cancers, developmental disorders, aging, and infectious diseases, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [3,4] . Estrogen, a key sex hormone, is instrumental in the development of seco

FAQs

Why is autophagy considered a cytoprotective mechanism in disease?

Autophagy helps cells cope with pathological stresses by maintaining intracellular mass and energy balance. It supports metabolism, growth, development, and immune function.

What role does estrogen play in variability of treatment responses involving autophagy?

The review links estrogen signaling strongly with autophagy, suggesting estrogen contributes to different biological outcomes. Estrogen’s diverse effects can influence how autophagy behaves across diseases.

How does the review describe the estrogen–autophagy relationship in cancer?

It summarizes mechanisms showing dual cytoprotective effects and highlights how different ligands, disease contexts, and cell types shape the axis. It also discusses estrogen antagonists and other estrogen-related factors that can affect autophagy and tumor outcomes.

Sep 21, 2026

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