Work

Hupehenine suppresses tumor cell phenotypes and modulates macrophage marker profiles in a diabeticmimetic colorectal cancer model

Year: 2026

Type: article

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: 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.

Source: Frontiers in Pharmacology

DOI: 10.3389/fphar.2026.1962620