PERK prevents hepatic lipotoxicity by activating the p62-ULK1 axis-mediated noncanonical KEAP1-Nrf2 pathway.

Hepatic lipotoxicity is a crucial factor in nonalcoholic steatohepatitis resulting from excessive saturated fatty acid-induced reactive oxygen species (ROS)-mediated cell death, which is associated with the accumulation of endoplasmic reticulum (ER) stress in the liver. The unfolded protein response (UPR) alleviates ER stress by restoring ER protein folding homeostasis. However, whether UPR contributes ROS elimination under lipotoxicity remains unclear. The Kelch like ECH-associated protein 1 (KEAP1)-nuclear factor, erythroid 2 like 2 (Nrf2) pathway provides antioxidant defense against lipotoxic stress by eliminating ROS and can be activated by the p62-Unc-51 like autophagy activating kinase 1 (ULK1) axis. However, the upstream molecular regulator of the p62-ULK1 axis-induced KEAP1-Nrf2 pathway in the same context remains unidentified. Here, we demonstrated that PKR-like ER kinase (PERK), a UPR sensor, directly phosphorylates p62 and ULK1, thereby activating the noncanonical KEAP1-Nrf2 pathway. We also elucidated the molecular mechanism underlying the PERK-mediated p62-ULK1 axis-dependent noncanonical KEAP1-Nrf2 pathway, which could represent a promising therapeutic strategy against hepatic lipotoxicity.