Available online 12 April 2025, 101301

SNX10 knockdown promotes DEPDC5 lysosome degradation in normal human IECs.

α-hederin interacts with SNX10 and DEPDC5 with a high affinity.

α-hederin reduces the binding between SNX10 and DEPDC5.

α-hederin inhibits the lysosomal degradation of DEPDC5.

Colorectal cancer (CRC) originates from biological events caused by gene mutations in normal intestinal epithelial cells (IECs). Sorting nexin 10 (SNX10) is a tumor suppressor in CRC that is involved in regulating chaperone-mediated autophagy (CMA) activity, which is implicated in the pathogenesis of CRC and glycolysis process. DEP domain containing 5 (DEPDC5) is a negative upstream regulator of mammalian target of rapamycin complex 1 (mTORC1). α-hederin has anti-CRC effects. We previously found that SNX10 knockdown in normal human IECs promoted glycolysis and decreased DEPDC5 expression, which was reversed by α-hederin. However, the specific mechanism has not yet been elucidated. Here, we aimed to investigate the specific regulatory mechanism of SNX10 on DEPDC5 expression, and the action of α-hederin on this process. We demonstrated that the degradation of DEPDC5 protein was accelerated after SNX10 knockdown, causing the activation of the mTORC1 pathway, which relied on CMA activation and lysosomal function enhancement. SNX10 interacted with DEPDC5 and recruited it to lysosomes for degradation, and the glycolysis level mediated by mTORC1 was elevated. Additionally, these phenotypes in shSNX10 IECs were compromised by SNX10 rescue. Moreover, α-hederin bound to the SNX10–DEPDC5 complex and impaired the interaction between SNX10 and DEPDC5, thereby inhibiting CMA-mediated DEPDC5 degradation, impairing the aberrant activation of mTORC1 signaling, and eventually reversing the elevation of glycolysis caused by SNX10 knockdown. Overall, we are the first to demonstrate that SNX10-mediated DEPDC5 degradation is a novel strategy for malignant transformation of normal human IECs, with α-hederin regulated during this process.

α-hederin

IECs

SNX10

DEPDC5

chaperone-mediated autophagy

lysosome

© 2025 The Author(s). Published by Elsevier B.V. on behalf of Xi’an Jiaotong University.