Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities

Nat Rev Drug Discov. 2008 Dec;7(12):1013-30. doi: 10.1038/nrd2755.


The accumulation of unfolded proteins in the endoplasmic reticulum (ER) represents a cellular stress induced by multiple stimuli and pathological conditions. These include hypoxia, oxidative injury, high-fat diet, hypoglycaemia, protein inclusion bodies and viral infection. ER stress triggers an evolutionarily conserved series of signal-transduction events, which constitutes the unfolded protein response. These signalling events aim to ameliorate the accumulation of unfolded proteins in the ER; however, when these events are severe or protracted they can induce cell death. With the increasing recognition of an association between ER stress and human diseases, and with the improved understanding of the diverse underlying molecular mechanisms, novel targets for drug discovery and new strategies for therapeutic intervention are beginning to emerge.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / physiology*
  • Cell Death / physiology*
  • Drug Design
  • Endoplasmic Reticulum / physiology*
  • Humans
  • Molecular Chaperones / physiology
  • Neoplasms / drug therapy
  • Neoplasms / physiopathology*
  • Neurodegenerative Diseases / physiopathology
  • Oxidative Stress
  • Protein Denaturation
  • Protein Folding
  • Reperfusion Injury / physiopathology
  • Signal Transduction
  • Stress, Physiological
  • eIF-2 Kinase / metabolism


  • Antineoplastic Agents
  • Molecular Chaperones
  • PERK kinase
  • eIF-2 Kinase