Lysosomal Membrane Permeabilization is Involved in CYP2E1-Induced Apoptosis in Hepatocellular Carcinoma Cells

• CYP2E1 overexpression induces LMP and subsequent apoptosis in HCC cells. • CYP2E1 upregulates NEU4, causing deglycosylation and degradation of LAMP1/2. • Low CYP2E1 in HCC patients correlates with high LAMP1/2 glycosylation. 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.