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

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.

Dickkopf-1 (DKK1) blockade mitigates osteogenesis imperfecta (OI) related bone disease

“…This stress leads to significant osteoblast apoptosis, contributing to the disease’s severe bone phenotype and lethality. Although DKK1-AS may enhance collagen I expression, it could potentially exacerbate the endoplasmic reticulum stress phenotype (Yuan et al 2024 ). Therefore, further refinement of DKK1-AS to encompass all associated molecular pathologies in severe type OI is necessary.…”

Cellular Distribution and Ultrastructural Changes in HaCaT Cells, Induced by Podophyllotoxin and Its Novel Fluorescent Derivative, Supported by the Molecular Docking Studies

“…ER stress triggers a complex cellular reaction known as Unfolded Protein Response (UPR), which aims to restore ER homeostasis [ 39 ]. However, if UPR fails and/or ER stress is prolonged, it eventually leads to caspase activation and initiation of programmed cell death [ 40 ].…”