EIF2AK3 (PERK) is a metabolic-stress sensing protein kinase that serves as a critical effector of the integrated stress response (ISR) and unfolded protein response (UPR) 1. Upon sensing misfolded proteins in the endoplasmic reticulum, PERK phosphorylates eIF2α, globally attenuating cap-dependent translation while selectively promoting translation of stress-response mRNAs including ATF4 2. This phosphorylation initiates adaptive programs that reprogram cellular metabolism and proteostasis 3. Beyond classical UPR signaling, PERK functions as a direct receptor for the metabolite trimethylamine N-oxide (TMAO), activating the PERK-eIF2α axis to promote metabolic dysfunction 4. During ER stress, PERK-eIF2α signaling increases mitochondrial bioenergetics by promoting ATF4-mediated expression of supercomplex assembly factors, enhancing oxidative phosphorylation 5. Notably, mitochondrial protein ATAD3A selectively inhibits PERK signaling at mitochondria-ER contact sites, protecting mitochondrial translation from ER stress-induced repression 6. Additionally, STING-PERK-eIF2α represents a non-canonical innate immune pathway critical for cellular senescence and organ fibrosis 7. PERK dysfunction causes Wolcott-Rallison syndrome, highlighting its essential role in human health.