Endoplasmic reticulum stress and proteostasis pathways (UDCA-mediated) (ER stress/Proteostasis (UDCA))

The endoplasmic reticulum (ER) stress and proteostasis pathways mediated by ursodeoxycholic acid (UDCA) represent a critical therapeutic axis for addressing protein misfolding and cellular stress. UDCA and its derivative tauroursodeoxycholic acid (TUDCA) function as chemical chaperones that stabilize protein folding, thereby mitigating the Unfolded Protein Response (UPR) and preventing apoptosis (Kusaczuk, 2019). This mechanism is integrated with bile acid signaling through receptors like the Farnesoid X Receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5), as well as transporters such as the Apical Sodium-dependent Bile acid Transporter (ASBT) (Vaz & Ferdinandusse, 2017). While traditionally utilized in cholestatic liver diseases to protect hepatocytes from bile acid-induced toxicity, this pathway is now a major focus in neurodegeneration research, particularly for Parkinson's and Alzheimer's diseases, where ER stress is a primary driver of pathology (Mortiboys et al., 2015). Drugs targeting this pathway aim to restore cellular proteostasis and provide cytoprotection across a range of metabolic and degenerative conditions.

Other names

UDCA-mediated ER stress modulationBile acid-regulated proteostasisTUDCA-mediated UPR inhibitionBile acid transporter-mediated proteostasis

Ursodeoxycholic acid (UDCA) and its taurine-conjugated derivative (TUDCA) act as chemical chaperones to enhance protein folding capacity and reduce the activation of Unfolded Protein Response (UPR) sensors, including PERK, IRE1, and ATF6. They also modulate bile acid receptors such as the Farnesoid X Receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5), as well as transporters like the Apical Sodium-dependent Bile acid Transporter (ASBT), to regulate metabolic flux, prevent apoptosis, and maintain cellular homeostasis (Kusaczuk, 2019; Vaz & Ferdinandusse, 2017).