Comment on “α-hederin decreases the glycolysis level in intestinal epithelial cells via SNX10-mediated DEPDC5 degradation”

Colorectal cancer (CRC) represents a global health challenge with significant societal burden, ranking among the most prevalent and lethal malignancies worldwide. Despite advances in understanding CRC pathogenesis, its molecular mechanisms remain incompletely elucidated. Intestinal epithelial cells (IECs), the primary sites of CRC initiation, undergo genetic susceptibility alterations and mutations that drive carcinogenesis, highlighting the critical need to investigate IEC gene functions for identifying preventive targets.

Sorting nexin 10 (SNX10) is considered as a CRC susceptibility candidate and tumor suppressor during colorectal carcinogenesis [1]. This protein maintains endosomal/lysosomal homeostasis and critically regulates chaperone-mediated autophagy (CMA), a lysosome-dependent selective degradation pathway implicated in CRC development. Metabolic reprogramming constitutes a hallmark of malignancy, frequently involving pathway remodeling, key enzyme upregulation, and metabolic mode shifts to support rapid tumor growth. DEP domain-containing 5 (DEPDC5) serves as an upstream negative regulator of mammalian target of rapamycin complex 1 (mTORC1), the central cellular energy sensor coordinating metabolic processes. Recent evidence identifies DEPDC5 as a novel tumor suppressor of gastrointestinal mesenchymal tumors [2], with reduced expression in CRC tissues correlating with poorer patient survival. Nevertheless, the regulatory mechanisms governing DEPDC5 in tumorigenesis remain unknown.

Traditional Chinese medicine (TCM) compounds are gaining prominence in cancer prevention due to favorable safety profiles, low toxicity, good tolerability, and chemopreventive potential. α-hederin, a pentacyclic triterpenoid saponin from Fructus Akebia exhibits broad anticancer properties [3]. In CRC models, it induces apoptosis through reactive oxygen species (ROS)-activated mitochondrial signaling, provokes G2/M cell cycle arrest via nuclear factor kappaB (NF-κB) pathway inhibition, and enhances chemosensitivity to agents like 5-fluorouracil.

The team of Prof. Shen from Nanjing University of Chinese Medicine, China previously found that SNX10 regulates glucose metabolism in normal human IECs. They observed that knockdown of SNX10 in IECs is accompanied by a decrease in DEPDC5 expression, while the natural compound α-hederin exerts a regulatory effect on the expression of both SNX10 and DEPDC5 [4]. Here, in their publication in Journal of Pharmaceutical Analysis (Volume 15, Issue 12, December 2025), they further elaborated on the role of the SNX10-mediated DEPDC5 degradation pathway (the SNX10/DEPDC5 axis) in modulating glycolysis during malignant transformation of normal human IECs, as well as the role of α-hederin in these biological processes [5].

To comprehensively investigate the biological function of SNX10 in normal human IECs, they designed an SNX10-overexpression plasmid for rescue experiments in SNX10 knockdown IECs. This study established SNX10’s essential role in maintaining DEPDC5 protein stability at the post-translational level. In subsequent explorations, they were the first to report that DEPDC5 contains two canonical chaperone-mediated autophagy (CMA) motifs (QKVEF and VRLEQ) across different species. They then constructed a full-length DEPDC5 plasmid labeled with a Flag tag and validated the physical interactions between DEPDC5 and both SNX10 and CMA-related proteins, thus identifying DEPDC5 as a novel SNX10-interacting protein and a new CMA substrate. Notably, they were also the first to reveal that SNX10 regulates DEPDC5 degradation through lysosomal pathways, which promotes mTORC1 activation in normal human IECs and thereby enhances glycolysis levels. This suggests that SNX10-mediated DEPDC5 degradation may represent a novel driver of malignant transformation in normal human IECs. Moreover, α-hederin impairs the SNX10-DEPDC5 interaction, inhibiting DEPDC5’s lysosomal degradation and ultimately suppressing glycolysis. The authors had made great efforts to elucidate this specific mechanism by which SNX10 regulates DEPDC5 expression and controls lysosomal function, and how α-hederin modulates this process. Further, their work investigates the potential crosstalk between SNX10-mediated CMA and glycolysis, which may represent a novel biological event during the CRC prevention process triggered by α-hederin.

It should be noted that the research relies on in vitro cell line models, which cannot fully replicate the complex in vivo microenvironment and physiological conditions of CRC progression. Additionally, the specificity of α-hederin’s action and its potential off-target effects warrant more detailed investigation in future studies to fully assess its therapeutic potential and safety profile.

Building upon these promising findings, future research should prioritize the in vivo validation of the SNX10/DEPDC5 axis in relevant CRC animal models. Comprehensive preclinical assessments of α-hederin, encompassing its efficacy, pharmacokinetics, pharmacodynamics, and toxicology, are essential steps toward translational application. Exploring the biomarker potential of the SNX10/DEPDC5 axis merits exploration, as their expression patterns may serve as predictive indicators for CRC risk, progression, or treatment response. Mechanistically, elucidating potential crosstalk between the SNX10/DEPDC5 pathway and other established cancer hallmarks, such as immune evasion, and genome instability, will provide a more integrated understanding of its role in CRC initiation and progression.

Collectively, these findings establish a theoretical foundation for intercepting intestinal epithelial carcinogenesis and address a crucial gap in understanding CRC initiation. The study further suggests that SNX10-targeted gene therapies or α-hederin-based regimens could potentially define progression stages in CRC development.