GPX8 (Glutathione Peroxidase 8) is an endoplasmic reticulum (ER)-resident glutathione peroxidase that catalyzes the reduction of hydrogen peroxide, organic hydroperoxides, and lipid peroxides using glutathione as the electron donor[@brigeliusfloh2013]. GPX8 is unique among glutathione peroxidases in that it contains an N-terminal transmembrane domain that anchors it to the ER membrane[@bosello2012]. This localization positions GPX8 as a critical component of ER redox homeostasis and the [unfolded protein response](/entities/unfolded-protein-response) (UPR).
Function
GPX8 exhibits several key functions:
ER Oxidative Stress Defense: Reduces peroxides in the ER lumen, protecting against oxidative protein damage[@ramming2020]
UPR Regulation: Plays a role in modulating the PERK and IRE1α branches of the unfolded protein response[@chen2019]
Protein Folding: Maintains ER redox balance necessary for proper disulfide bond formation
Calcium Homeostasis: Helps regulate ER calcium storage through oxidative stress mitigation[@li2018]
Disease Associations
Alzheimer's Disease
GPX8 expression is downregulated in AD brain tissue, particularly in regions vulnerable to amyloid pathology[@hwang2017]. Loss of GPX8 leads to increased ER stress and activation of pro-apoptotic pathways. The enzyme protects against [Aβ](/proteins/amyloid-beta)-induced neuronal death through reduction of oxidative stress[@zhang2019].
Parkinson's Disease
In PD models, GPX8 protects against oxidative stress-induced dopaminergic neuron death. Studies show that GPX8 overexpression reduces 6-OHDA toxicity and preserves mitochondrial function[@chen2020].
Metabolic Disorders
GPX8 is implicated in non-alcoholic fatty liver disease (NAFLD) and insulin resistance, conditions that are risk factors for neurodegenerative disease[@liu2021].
Expression Pattern
GPX8 shows highest expression in:
Liver (hepatocytes)
Kidney (proximal tubules)
Small intestine (enterocytes)
Lower expression in brain ([neurons](/entities/neurons), astrocytes)
Therapeutic Implications
ER-Targeted Antioxidants: GPX8 as a therapeutic target for reducing ER oxidative stress
Gene Therapy: AAV-mediated GPX8 delivery for neurodegenerative diseases
Small Molecule Inducers: Compounds that upregulate GPX8 expression