Hupehenine suppresses tumor cell phenotypes and modulates macrophage marker profiles in a diabeticmimetic colorectal cancer model
- 1Xuzhou Clinical College of Xuzhou Medical University, Xuzhou Central Hospital
- 2Lab of Cell Biology, School of Life Sciences, Jiangsu Normal University
Abstract
Background: Diabetes is associated with increased colorectal cancer (CRC) risk and mortality, but the molecular links remain incompletely understood. We aimed to characterize shared molecular features of diabetes and CRC, and identify compounds capable of modulating the candidate axis at this interface.
Methods: Shared disease-associated genes were identified using integrated bioinformatics and protein-protein interaction network analysis, followed by analyses of TCGA and single-cell RNA-sequencing data. Deep learning-based (DeepPurpose) and structure-based (AutoDock Vina) virtual screening were used to prioritize multi-target ligands. Binding was assessed by surface plasmon resonance (SPR) and molecular dynamics simulations. Cellular effects were evaluated in a diabetic-mimetic model using high glucose, insulin, and palmitic acid (three factors; TF), with HCT116 cells and THP-1-derived macrophages.
Results: The IL1β-CXCL8-CXCR2 axis was prioritized as a candidate inflammatory module at the diabetes-CRC interface. TCGA and single-cell RNA-seq analyses associated axis-related expression with immune infiltration and macrophage polarization-related transcriptional signatures; higher axis expression was also associated with longer overall survival. Hupehenine (HU), a steroidal alkaloid, was identified as a multi-target ligand engaging IL1β, CXCL8, and CXCR2. SPR showed concentration-dependent binding (KD: CXCR2, 505 nM; CXCL8, 2.2 μM; IL1β, 12.7 μM) and interference with CXCL8-CXCR2 binding. In a diabetic-mimetic model, HU reduced HCT116 cell viability, migration, and invasion. TF-conditioned cells were more sensitive to HU than non-TF cells, whereas a corresponding increase in sensitivity was not observed for 5-fluorouracil or oxaliplatin. HU also decreased M2-associated and increased M1-associated macrophage markers.
Conclusion: These findings support the IL1β-CXCL8-CXCR2 axis as a candidate immunomodulatory module at the diabetes-CRC interface and identify HU as an in vitro multi-target ligand. The observed changes in macrophage markers and differential sensitivity under diabetic-mimetic conditions warrant further mechanistic and preclinical evaluation, including direct assessment of macrophage function.
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BibTeX
@article{zhu2026hupehenine,
title = {{Hupehenine suppresses tumor cell phenotypes and modulates macrophage marker profiles in a diabeticmimetic colorectal cancer model}},
author = {Ming Qi Zhu and Zi Tong Shi and Hong Mei Hu and Qi Dong Xue and Xin Yu Gu and Xin Cheng Li and Qiu Yan Wang and Yan Zhao and You Wei Zhang and Ji Zhong Zhao},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1962620},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1962620/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Hupehenine suppresses tumor cell phenotypes and modulates macrophage marker profiles in a diabeticmimetic colorectal cancer model
AU - Ming Qi Zhu
AU - Zi Tong Shi
AU - Hong Mei Hu
AU - Qi Dong Xue
AU - Xin Yu Gu
AU - Xin Cheng Li
AU - Qiu Yan Wang
AU - Yan Zhao
AU - You Wei Zhang
AU - Ji Zhong Zhao
PY - 2026
DA - 2026/10/20
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1962620
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1962620/full
AB - Background: Diabetes is associated with increased colorectal cancer (CRC) risk and mortality, but the molecular links remain incompletely understood. We aimed to characterize shared molecular features of diabetes and CRC, and identify compounds capable of modulating the candidate axis at this interface. Methods: Shared disease-associated genes were identified using integrated bioinformatics and protein-protein interaction network analysis, followed by analyses of TCGA and single-cell RNA-sequencing data. Deep learning-based (DeepPurpose) and structure-based (AutoDock Vina) virtual screening were used to prioritize multi-target ligands. Binding was assessed by surface plasmon resonance (SPR) and molecular dynamics simulations. Cellular effects were evaluated in a diabetic-mimetic model using high glucose, insulin, and palmitic acid (three factors; TF), with HCT116 cells and THP-1-derived macrophages. Results: The IL1β-CXCL8-CXCR2 axis was prioritized as a candidate inflammatory module at the diabetes-CRC interface. TCGA and single-cell RNA-seq analyses associated axis-related expression with immune infiltration and macrophage polarization-related transcriptional signatures; higher axis expression was also associated with longer overall survival. Hupehenine (HU), a steroidal alkaloid, was identified as a multi-target ligand engaging IL1β, CXCL8, and CXCR2. SPR showed concentration-dependent binding (KD: CXCR2, 505 nM; CXCL8, 2.2 μM; IL1β, 12.7 μM) and interference with CXCL8-CXCR2 binding. In a diabetic-mimetic model, HU reduced HCT116 cell viability, migration, and invasion. TF-conditioned cells were more sensitive to HU than non-TF cells, whereas a corresponding increase in sensitivity was not observed for 5-fluorouracil or oxaliplatin. HU also decreased M2-associated and increased M1-associated macrophage markers. Conclusion: These findings support the IL1β-CXCL8-CXCR2 axis as a candidate immunomodulatory module at the diabetes-CRC interface and identify HU as an in vitro multi-target ligand. The observed changes in macrophage markers and differential sensitivity under diabetic-mimetic conditions warrant further mechanistic and preclinical evaluation, including direct assessment of macrophage function.
SN - 1663-9812
ER -