Activation of unfolded protein response pathways promotes keratinocyte differentiation and ameliorates psoriasis phenotypes

Psoriasis is a chronic inflammatory skin disorder characterized by abnormal keratinocyte (KC) differentiation and proliferation, along with infiltration of various immune cells into the skin. Both internal and external perturbations can disrupt endoplasmic reticulum (ER) homeostasis, leading to ER stress and activation of the unfolded protein response (UPR) pathways. Although the UPR is known to participate in normal epidermal KC differentiation, its regulatory role in psoriasis remains poorly understood. In this study, we observed significant attenuation of UPR pathways specifically IRE1α-XBP1s and PERK signaling in psoriasis lesions. Administration of ER stress inducers (TM and BFA) alleviated psoriasis-like phenotypes in an imiquimod (IMQ)-induced mouse model. Furthermore, knockdown of Grp78 in KCs activated both IRE1α-XBP1s and PERK pathways, thereby improving KC differentiation in vitro. Notably, combining of Grp78 knockdown with ER stress inducers synergistically enhanced KC differentiation through UPR activation. Together, these findings indicate that the ER stress response promotes epidermal KC differentiation. Targeted activation of UPR pathways may thus represent a novel therapeutic strategy to improve KC differentiation in psoriasis.