Journal Club 2026.10.02

Leave a Comment / By Diwas Rawal / 2026/10/01

Endoplasmic Reticulum Stress in the Keratinocytes Contributes to Chronic Itch by Activation of Lipocalin 2/MC4R/TRPV1 Pathway

Wei Ge^# 1 2, Yu Feng^# 3, Li Zhang^# 4, Qian-Liang Wang^# 1, Cheng-Wei Zhang⁵, Zhi-Hong Wang⁶, Guo-Kun Zhou⁷, Shi-Yu Sun⁷, Xiu-Hua Miao⁸, Tong Liu⁹, Bin Wu¹⁰, Jun Yan¹¹

Affiliations

¹Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
²Department of Orthopedics, Yancheng First People’s Hospital, Affiliated Hospital of Nanjing University Medical School, Yancheng, 224000, China.
³Department of Rheumatology and Immunology, The Fourth Affiliated Hospital of Soochow University, Suzhou, 215000, China.
⁴Department of Anesthesiology, The First People’s Hospital of Kunshan Affiliated with Jiangsu University, Kunshan, 215300, China.
⁵Department of Thoracic Surgery, Capital Medical University, Electric Power Teaching Hospital, Beijing, 100073, China.
⁶Cambridge-Suda Genomic Resource Center, Suzhou Medical College, Soochow University, Suzhou, 215000, China.
⁷Institute of Pain Medicine and Special Environmental Medicine, Nantong University, Nantong, 226001, China.
⁸Department of Pain Management, Affiliated Hospital and Medical School of Nantong University, Nantong, 226001, China.
⁹Institute of Pain Medicine and Special Environmental Medicine, Nantong University, Nantong, 226001, China. tongliu@ntu.edu.cn.
¹⁰Department of Anesthesiology and Pain Rehabilitation, Cardiopulmonary and Critical Care Rehabilitation Center, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Tongji University School of Medicine, Shanghai, 200092, China. wubin0108@hotmail.com.
¹¹Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China. cxyanjun@hotmail.com.

^#Contributed equally.

Abstract

Endoplasmic reticulum (ER) stress plays a significant role in chronic pain, but its potential involvement in chronic itch remains largely unexplored and poorly understood. In the current study, we investigated whether ER stress signaling in keratinocytes contributes to the pathogenesis of chronic itch. Our behavioral tests showed that the ER stress inhibitor 4-PBA attenuated itch-related behaviors in both acute and chronic itching mouse models, and reduced compound 48/80 and serotonin-induced activity of dorsal root ganglion (DRG) neurons. qPCR and western blotting revealed that the ER stress-related proteins and Lipocalin-2 (LCN2) were significantly elevated in the affected skin under chronic itch conditions and in cultured keratinocyte HaCaT cells and mice skin keratinocytes. The ELISA test showed that the level of LCN2 increased significantly in plasma but not in DRG tissue, from both acetone-ether-water (AEW) induced dry skin and imiquimod (IMQ) induced psoriasis model mice. Current clamp recording demonstrated that LCN2 induced hyperexcitability in dorsal root ganglia neurons, which could be abolished by HS024, the inhibitor of melanocortin receptor 4 (MC4R). In addition, pharmacological inhibition of transient receptor potential vanilloid 1 (TRPV1) or TRPV1 knockout blocked LCN2-induced hyperexcitability in DRG neurons. In conclusion, this study demonstrated that keratinocyte ER stress is involved in chronic itch genesis by releasing LCN2, which sensitized primary sensory neurons via TRPV1. These findings suggested that inhibition of ER stress in keratinocytes could be a promising therapeutic strategy for treating chronic itch.

Keywords: Endoplasmic reticulum stress; Itch; Keratinocyte; LCN2; TRPV1.