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Updated: Apr 23, 2026
A Three-dimensional Model of Spheroids to Study Colon Cancer Stem Cells
Published on: January 22, 2021
The MIF-CD74 axis drives colorectal cancer via glycolytic reprogramming and is targeted by a novel small-molecule
Jinwei Lou1,2, Yuhan Chen1,2, Yue Li1
1General Clinical Research Center, Nanjing First Hospital, China Pharmaceutical University, Nanjing, Jiangsu, 211122, China.
Background:
Macrophage migration inhibitory factor (MIF) promotes inflammation, regulates immune responses and chemotherapy resistance in the tumor microenvironment. However, its mechanism of action in colorectal cancer (CRC) metabolic reprogramming and targeted therapeutic potential remain unclear. This study aims to investigate the function, mechanism, and targeted therapeutic potential of MIF in CRC.
Methods:
Data were integrated from TCGA, GTEx, CPTAC, and HPA databases with clinical sample validation. Single-cell sequencing analysis (datasets GSE166555 and GSE144735) was performed, alongside functional assays and mechanistic studies. A novel high-potency MIF inhibitor was identified through virtual screening and validated in vitro and in vivo.
Results:
MIF expression was found to be significantly elevated in CRC tissues and cell lines, correlating with poor overall survival (OS) and disease-specific survival (DSS). Single-cell sequencing confirmed malignant epithelial cells as the primary MIF source. Functional assays demonstrated that MIF knockout suppressed CRC cell proliferation, migration, and tumor growth in vivo, while MIF overexpression promoted these effects. Mechanistically, MIF binds CD74 to upregulate glycolytic enzymes (HK2, PKM2, LDHA), enhancing glucose uptake and lactate/pyruvate production, thereby driving the Warburg effect and CRC progression. Virtual screening identified a novel high-potency MIF inhibitor, F3277-0933 (IC50 = 8.284 μM). In vitro and in vivo, F3277-0933 surpassed the classical inhibitor ISO-1 in suppressing MIF-driven glycolytic reprogramming and proliferation.
Conclusion:
This study elucidates a novel mechanism by which the MIF-CD74 axis drives CRC progression through glycolytic reprogramming and provides robust preclinical evidence for developing MIF-targeted therapies.
Insights
Macrophage migration inhibitory factor (MIF) drives colorectal cancer (CRC) progression by reprogramming glucose metabolism. A novel inhibitor targeting the MIF-CD74 pathway shows promising therapeutic potential for CRC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Reprogramming
Background:
- Macrophage migration inhibitory factor (MIF) is implicated in inflammation and immune responses.
- Its role in colorectal cancer (CRC) metabolic reprogramming and therapeutic potential are not fully understood.
Purpose of the Study:
- To investigate the function and mechanism of MIF in CRC.
- To explore the targeted therapeutic potential of MIF in CRC.
Main Methods:
- Integrated multi-omics data (TCGA, GTEx, CPTAC, HPA) and clinical samples.
- Performed single-cell sequencing, functional assays, and mechanistic studies.
- Identified and validated a novel MIF inhibitor via virtual screening.
Main Results:
- Elevated MIF expression in CRC correlates with poor survival.
- MIF promotes CRC cell proliferation, migration, and tumor growth.
- MIF-CD74 axis upregulates glycolytic enzymes, driving the Warburg effect in CRC.
- A novel inhibitor, F3277-0933, effectively suppressed MIF-driven glycolysis and proliferation.
Conclusions:
- The MIF-CD74 axis drives CRC progression via glycolytic reprogramming.
- This study provides preclinical evidence for MIF-targeted therapies in CRC.
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