Endoplasmic reticulum stress and therapeutic strategies in metabolic, neurodegenerative diseases and cancer

Sep 22, 2026

Endoplasmic reticulum stress arises when unfolded or misfolded proteins accumulate in the ER due to genetic and environmental factors. This triggers the unfolded protein response (UPR) through three signaling arms—IRE1, PERK, and ATF6—to increase protein folding capacity and restore ER homeostasis. When stress persists, the UPR shifts toward cell death and initiates inflammatory cascades, promoting cancer, neurodegenerative disorders, and diabetes. Reducing UPR signaling correlates with diminished disease-cell proliferation.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Abstract

Introduction

Protein homeostasis and ER stress

UPR activation and disease connection

Signaling pathway involved in ER stress

UPR transmembrane sensors (PERK, ATF6, IRE1)

GRP78/BiP regulation

IRE1 signaling pathway

Yuan et al. Molecular Medicine (2024) 30:40 [https://doi.org/10.1186/s10020-024-00808-9](https://doi.org/10.1186/s10020-024-00808-9) Molecular Medicine REVIEW Open Access Endoplasmic reticulum stress and therapeutic strategies in metabolic, neurodegenerative diseases and cancer Siqi Yuan 1†, Dan She 1†, Shangming Jiang 1†, Nan Deng 1, Jiayi Peng 1 and Ling Ma 1* Abstract The accumulation of unfolded or misfolded proteins within the endoplasmic reticulum (ER), due to genetic determinants and extrinsic environmental factors, leads to endoplasmic reticulum stress (ER stress) . As ER stress ensues, the unfolded protein response (UPR), comprising three signaling pathways—inositol-requiring enzyme 1, protein kinase R-like endoplasmic reticulum kinase, and activating transcription factor 6 promptly activates to enhance the ER’s protein-folding capacity and restore ER homeostasis. However, prolonged ER stress levels propels the UPR towards cellular demise and the subsequent inflammatory cascade, contributing to the development of human diseases, including cancer, neurodegenerative disorders, and diabetes. Notably, increased expression of all three UPR signaling pathways has been observed in these pathologies, and reduction in signaling molecule expression correlates with decreased proliferation of disease-associated target cells. Consequently, therapeutic strategies targeting ER stress-related interventions have attracted significant research interest. In this review, we elucidate the critical role of ER stress in cancer, metabolic, and neurodegenerative diseases, offering novel therapeutic approaches for these conditions. Keywords Endoplasmic reticulum stress, Signaling pathway, Cancer, Neurodegenerative diseases, Metabolic, Therapeutic strategies Introduction Proteins are essential cellular components critical for maintaining and regulating biological functions. Deviations in protein expression, folding, function, or localization can significantly affect the biological functions of organisms(Jayaraj et al. 2020). The ER is the primary site for protein and lipid synthesis and calcium ion storage †Siqi Yuan, Dan She and Shangming Jiang contributed equally to this work. *Correspondence: Ling Ma[malingxh@163.com](malingxh@163.com) 1Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, China in eukaryotic cells, playing a vital role in regulating protein secretion and synthesis. Under normal conditions, only correctly folded proteins are secreted, while genetic mutations or stress conditions, such as hypoxia and oxidative stress, lead to the formation of misfolded proteins. The accumulation of misfolded proteins induces ER stress and triggers the UPR, which relieves ER stress by enhancing the ER’s protein folding capacity and degrading misfolded proteins. Persistent ER stress ultimately leads to cell death(Walter and Ron 2011). Maintaining protein homeostasis is essential for the normal physiological activities of organisms. Chronic ER stress is increasingly recognized as a key factor in a growing number of human diseases(Dikic 2017). Research confirms that ER stress is activated in many human © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permi

FAQs

What causes endoplasmic reticulum (ER) stress?

ER stress is caused by the accumulation of unfolded or misfolded proteins in the ER, driven by genetic determinants and extrinsic environmental factors.

What is the unfolded protein response (UPR) and what does it do?

The UPR is activated by three signaling pathways (IRE1, PERK, and ATF6). It enhances the ER’s protein-folding capacity and helps restore ER homeostasis.

How does prolonged ER stress contribute to disease?

Prolonged ER stress pushes the UPR toward cellular demise and activates inflammatory cascades, contributing to cancer, neurodegenerative disorders, and diabetes.

Sep 22, 2026

Upload by Lucas Martin