The endoplasmic reticulum mediates essential processes such as protein
folding, transport, and post-translational modifications. Disruptions in
endoplasmic reticulum function can lead to the accumulation of unfolded
or misfolded proteins, initiating endoplasmic reticulum stress. This
stress activates the unfolded protein response, a multifaceted signaling
pathway aimed at restoring proteostasis, which is crucial for cellular
survival and fate determination. This review summarizes the current
knowledge of three major branches of the unfolded protein response: the
IRE1, PERK, and ATF6 signaling pathways. A key novel component in
endoplasmic reticulum stress adaptation is the redox-sensitive enzyme
glutathione peroxidase 8 (GPX8), which plays a dual role in detoxifying
hydrogen peroxide and supporting proper protein folding. By connecting
unfolded protein response branches, GPX8 reduces oxidative damage while
maintaining redox homeostasis, emphasizing its importance in endoplasmic
reticulum stability. Furthermore, plant glutathione peroxidases exhibit
parallel functions in endoplasmic reticulum redox homeostasis and
unfolded protein response activation, highlighting the evolutionary
conservation of this protective mechanism across kingdoms. Understanding
the intricate relationship between GPX8, endoplasmic reticulum stress,
and unfolded protein response signaling provides novel insights into
therapeutic strategies for diseases characterized by protein folding
defects and oxidative stress.