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

Zhibao Zhang, Mingyi Tan, Xin Liu, Wenhua Wang, Xiang Chen, Cong Peng, Shuang Zhao, Lisha Wu

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Article in Cell stress & chaperones, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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8 authors.

Zhibao ZhangDepartment of Dermatology, Xiangya Hospital, Central South University, Changsha, China, 410078; Hunan Provincial Key Laboratory of Skin Tumor and Psoriasis, Changsha, China, 410078; Changsha Central Hospital, Changsha, Hunan, China, 410014.

Mingyi TanDepartment of Dermatology, Xiangya Hospital, Central South University, Changsha, China, 410078; Hunan Provincial Key Laboratory of Skin Tumor and Psoriasis, Changsha, China, 410078.

Xin LiuDepartment of Dermatology, Xiangya Hospital, Central South University, Changsha, China, 410078; Hunan Provincial Key Laboratory of Skin Tumor and Psoriasis, Changsha, China, 410078.

Wenhua WangDepartment of Dermatology, Xiangya Hospital, Central South University, Changsha, China, 410078; Hunan Provincial Key Laboratory of Skin Tumor and Psoriasis, Changsha, China, 410078.

Xiang ChenDepartment of Dermatology, Xiangya Hospital, Central South University, Changsha, China, 410078; Hunan Provincial Key Laboratory of Skin Tumor and Psoriasis, Changsha, China, 410078; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China, 410078.

Cong PengDepartment of Dermatology, Xiangya Hospital, Central South University, Changsha, China, 410078; Hunan Provincial Key Laboratory of Skin Tumor and Psoriasis, Changsha, China, 410078.

Shuang ZhaoDepartment of Dermatology, Xiangya Hospital, Central South University, Changsha, China, 410078; Hunan Provincial Key Laboratory of Skin Tumor and Psoriasis, Changsha, China, 410078.

Lisha WuDepartment of Dermatology, Xiangya Hospital, Central South University, Changsha, China, 410078; Hunan Provincial Key Laboratory of Skin Tumor and Psoriasis, Changsha, China, 410078; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China, 410078; Institute of Medical Sciences, Xiangya Hospital, Central South University, Changsha, China, 410078. Electronic address: lishawu@csu.edu.cn.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

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.

Indexed as

Cell DifferentiationKeratinocytesPsoriasisUnfolded Protein ResponseAnimalsDisease Models, AnimaleIF-2 KinaseEndoplasmic Reticulum Chaperone BiPEndoplasmic Reticulum StressEndoribonucleasesHeat-Shock ProteinsHumansImiquimodMicePhenotypeProtein Serine-Threonine KinaseseIF-2 KinaseEndoplasmic Reticulum Chaperone BiPEndoribonucleasesErn1 protein, mouseHeat-Shock ProteinsHSPA5 protein, humanHspa5 protein, mouseImiquimodProtein Serine-Threonine KinasesX-Box Binding Protein 1Endoplasmic reticulum stressKeratinocyte differentiationPsoriasisUnfolded protein response

Identifiers

PMID41765076

DOI10.1016/j.cstres.2026.100163

PMCPMC12997330

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.