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Endoplasmic reticulum stress in disease pathogenesis: its implications for therapy

16 April 2026

Wei Siyu, Zhang Nan, Zhang Hao, Chen Zigui, Li Shuyu, Wu Wantao, Liu Zaoqu, Xia Zhiwei, Luo Peng, Cheng Quan

Summary

Plain-Language Summary

This study highlights that "ER stress," a cellular imbalance where cells struggle to properly fold proteins, is a fundamental factor in the development of many serious diseases, including cancer, heart disease, and neurodegenerative conditions. While our cells have natural mechanisms to cope, if this stress is severe or prolonged, it can lead to cell damage and disease progression. Understanding these ER stress pathways opens new doors for potential therapies.

Key Findings

  • Widespread Disease Link: ER stress is a critical cellular mechanism implicated in a broad spectrum of diseases, from cancer and metabolic disorders to cardiovascular, neurodegenerative, and autoimmune conditions.
  • Cellular Stress Response: Cells combat ER stress through the Unfolded Protein Response (UPR), a sophisticated system designed to restore balance and ensure proper protein function.
  • Harmful Overload: If ER stress is excessive or prolonged, the UPR can become overwhelmed, leading to detrimental effects like cell death, chronic inflammation, and the accumulation of damaged proteins, thus driving disease progression.
  • Cancer's Advantage: In cancer, ER stress not only helps shape the tumor environment but also assists cancer cells in evading the immune system, complicating treatment efforts.
  • Therapeutic Potential: Modulating these ER stress pathways is identified as a promising therapeutic strategy to restore cellular equilibrium and potentially improve treatment outcomes across various diseases.

Practical Takeaways for Nutrition and Longevity

While this review doesn't provide specific dietary interventions, understanding ER stress emphasizes the importance of overall cellular health:

  • Support Cellular Resilience: A balanced diet rich in whole foods, antioxidants (from fruits, vegetables), and healthy fats can help reduce general cellular stressors and support the cell's ability to cope with ER stress.
  • Reduce Inflammatory Burden: Chronic inflammation is linked to ER stress. Adopting an anti-inflammatory eating pattern (e.g., Mediterranean diet) can help lower systemic inflammation.
  • Mindful Protein Intake: As ER stress relates to protein folding, ensuring adequate, high-quality protein without excessive intake is important for overall cellular function.
  • Holistic Lifestyle: Beyond diet, regular physical activity, adequate sleep, and stress management are vital for maintaining cellular balance and reducing the chronic stress that can contribute to ER dysfunction and accelerated aging.

Study Limitations

This study is a review, meaning it integrates existing research findings rather than presenting new experimental data. Therefore, it focuses on theoretical connections and potential therapeutic targets, without providing novel insights from direct experimentation or specific intervention trials.

Abstract

Endoplasmic reticulum (ER) stress is a key cellular mechanism that is important in the development of many diseases, including cancer. Since the discovery of the unfolded protein response (UPR), research has greatly improved our understanding of how ER stress affects cellular functions, especially protein folding and adaptation to stress. The UPR consists of three main branches: IRE1, ATF6, and PERK, each of which is crucial for regulating stress responses, protein homeostasis, and apoptosis. These pathways normally help cells handle stress effectively; however, excessive or prolonged activation can lead to cell death and disease progression. In cancer, ER stress not only shapes the tumor environment but also supports immune evasion, making treatment more challenging. Moreover, ER stress is linked to a wide range of other diseases, including cardiovascular diseases, neurodegenerative disorders, metabolic issues, and autoimmune diseases. ER stress can cause inflammation, protein buildup, and disrupted immune responses in these cases. Targeting the pathways involved in ER stress is a promising therapeutic approach with the potential to reduce disease severity and improve treatment outcomes by restoring cellular balance. The current review systematically integrates current findings on the signaling pathways and regulatory mechanisms of ER stress, examines its role in a wide range of diseases, and explores potential therapeutic strategies aimed at modulating this response. By focusing on the complex relationship between ER stress and different diseases, this investigation aims to guide future research and clinical efforts targeting ER stress-related pathways.
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