Lysosomal membrane permeabilization is involved in CYP2E1-induced apoptosis in hepatocellular carcinoma cells

  • BBA Adv. 2026 May 16:9:100194. doi: 10.1016/j.bbadva.2026.100194.
Xuan Wang  1  2 ,  An Wang  1  2 ,  Huanhuan He  1  2 ,  Jiaqi Qiao  1  2 ,  Chengyi Wang  1  2 ,  Haiyuan Du  1  2 ,  Xiji Shu  1  3  4  5 ,  Binlian Sun  2  4  5 ,  Xiaoqing Chen  3 ,  Qiongxia Chen  1  3 ,  Xuan Huang  1 ,  Shaobo Hu  6 ,  Yuchen Liu  2  4  5 ,  Zhengqi Fu  1  2  3
Affiliations
  • 1. Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan 430056, China.
  • 2. Cancer Institute, School of Medicine, Jianghan University, Wuhan 430056, China.
  • 3. Hubei Provincial Demonstration Center for Experimental Medicine Education, School of Medicine, Jianghan University, Wuhan 430056, China.
  • 4. Hubei Key Laboratory of Cognitive and Affective Disorders, Jianghan University, Wuhan 430056, China.
  • 5. Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China.
  • 6. Liver transplant center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
PMID: 42211167 DOI: 10.1016/j.bbadva.2026.100194
Abstract

CYP2E1 expression is often negatively correlated with hepatocellular carcinoma (HCC) progression, and its overexpression induces Apoptosis in HCC cells. However, the underlying mechanism of CYP2E1 in Apoptosis induction remains unclear. Given the crucial role of lysosomal dysfunction through lysosomal membrane permeabilization (LMP) in promoting Apoptosis, this study aimed to investigate whether and how lysosomal dysfunction and LMP contribute to CYP2E1-induced Apoptosis in HCC. Here, we demonstrated that CYP2E1 overexpression induced LMP, leading to the translocation of Cathepsin D and subsequent Apoptosis in HCC cells. Notably, Cathepsin D Inhibitor attenuated CYP2E1 overexpression-induced LMP and Apoptosis. In addition, through sialidase Neuraminidase 4 (NEU4), CYP2E1 overexpression resulted in the deglycosylation and degradation of lysosome-associated membrane protein 1 and 2 (LAMP1/2), contributing to LMP and Apoptosis both in vitro and in vivo. Clinically, decreased CYP2E1 expression in the tumor tissues of HCC patients is strongly associated with upregulated LAMP1/2 expression and glycosylation. Collectively, our findings elucidate the role of LMP in CYP2E1-induced cell Apoptosis with the involvement of NEU4, providing novel insight for CYP2E1 function in Apoptosis.

Keywords
CYP2E1; Deglycosylation; Hepatocellular carcinoma cells; Lysosomal membrane permeabilization.
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