CERS6 promotes esophageal squamous cell carcinoma proliferation by increasing the stability of RPN1

作者：Wenjing Chen, Yuxin Zhai, Xiaoxiao Yang, Weizhe Zhang, Dan Gao, Xiaokun Zhao, Nannan Zhao, Yuhan Zhang, Qiang Yuan, Zhiying Zhao, Qiong Wu, Yifei Xie, Jimin Zhao, Zigang Dong, Kangdong Liu, Yanan Jiang · 发表于：Cell Death Discovery · 年份：2025 · DOI：10.1038/s41420-025-02727-y · 被引用次数：3 · 研究领域：Sphingolipid Metabolism and Signaling、Endoplasmic Reticulum Stress and Disease、Inflammasome and immune disorders

Esophageal squamous cell carcinoma (ESCC) is associated with poor prognosis because it is typically diagnosed at a moderate or advanced stage. Investigating the precise molecular mechanism of ESCC pathogenesis is essential for developing new therapeutic strategies. In this study, we demonstrated that ceramide synthase 6 (CERS6) was overexpressed and correlated with a worse prognosis in ESCC. Moreover, CERS6 promoted ESCC cell proliferation in vitro and in vivo. Mechanistically, CERS6 sustained the stability of ribophorin 1 (RPN1) by inhibiting its ubiquitination. Subsequently, CERS6 reduced endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) by activating the RPN1-inositol-requiring enzyme 1 (IRE1)-X-box binding protein 1 (XBP1) signaling pathway. Interestingly, the antisense oligonucleotides (ASOs) targeting CERS6 inhibited the growth of ESCC through the RPN1-IRE1-XBP1 signaling pathway. Collectively, our study reveals an unprecedented function and mechanism of CERS6, which is distinct from ceramide synthases, in the development of ESCC, highlighting its potential as a promising therapeutic target.