The endoplasmic reticulum (ER) stress response is a critical cellular mechanism involved in maintaining protein homeostasis and ensuring proper folding of newly synthesized proteins. Under conditions of ER stress, unfolded or misfolded proteins accumulate within the ER lumen, triggering a series of signaling pathways collectively known as the unfolded protein response (UPR). While the UPR is initially adaptive, prolonged or unresolved ER stress can lead to cellular dysfunction and contribute to the pathogenesis of various diseases. This review explores the intricate molecular mechanisms underlying the ER stress response and its implications for disease pathogenesis and pathophysiology. We examine the role of ER stress in the pathophysiology of diverse diseases, including neurodegenerative disorders, metabolic syndromes, cardiovascular diseases, and cancer. Furthermore, we discuss potential therapeutic strategies targeting the ER stress response to mitigate disease progression and improve clinical outcomes. A comprehensive understanding of the ER stress response and its contributions to disease pathology is essential for the development of novel therapeutic interventions and the advancement of personalized medicine approaches.

Endoplasmic reticulum stress, Unfolded protein response, Pathophysiology

Rathore S, Datta G, Kaur I, Malhotra P, Mohmmed A. Disruption of cellular homeostasis induces organelle stress and triggers apoptosis like cell-death pathways in malaria parasite. Cell Death Dis 2015;6:e1803.

Yerbury J, Stewart E, Wyatt A, Wilson M. Quality control of protein folding in extracellular space. EMBO Rep 2005;6(12):1131–6.

Chakrabarti A, Chen AW, Varner JD. A review of the mammalian unfolded protein response. Biotechnol Bioeng 2011;108(12):2777–93.

Kotas M, Medzhitov R. Homeostasis, inflammation, and disease susceptibility. Cell 2015;160(5):816–27.

van Parjis L, Perez VL, Abbas AK. Mechanisms of peripheral T cell tolerance. Novartis Found Symp 1998;215:5–14.

Abbas AK, Lohr J, Knoechel B, Nagabhushanam V. T cell tolerance and autoimmunity. Autoimmun Rev 2004;3(7–8):471–5.

van Wijk F, Cheroutre H. Mucosal T cells in gut homeostasis and inflammation. Expert Rev Clin Immunol 2010;6(4):559–66.

Rock K, Kono H. The inflammatory response to cell death. Annu Rev Pathol 2008;3:99–126.

Chovatiya R, Medzhitov R. Stress, inflammation, and defense of homeostasis. Mol Cell 2014;54(2):281–8.

Lin JH, Walter P, Yen TS. Endoplasmic reticulum stress in disease pathogenesis. Annu Rev Pathol 2008;3:399–425.

Saraogi I, Shan SO. Molecular mechanism of co-translational protein targeting by the signal recognition particle. Traffic 2011;12:535–42.

Zimmerman R, Eyrisch S, Ahmad M, Helms V. Protein translocation across the ER membrane. Biochim Biophys Acta 2010;1808:912–24.