Targeting LIF With Cyclovirobuxine D to Suppress Tumor Progression via LIF/p38MAPK/p62‐Modulated Mitophagy in Hepatocellular Carcinoma
ABSTRACT Leukemia inhibitory factor (LIF) exerts an oncogenic function in several types of cancer, including hepatocellular carcinoma (HCC). However, small‐molecule inhibitors of LIF haven't been established. Here, we identified that LIF was remarkably overexpressed in HCC by multi‐omics approa...
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| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-06-01
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| Series: | MedComm |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/mco2.70227 |
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| Summary: | ABSTRACT Leukemia inhibitory factor (LIF) exerts an oncogenic function in several types of cancer, including hepatocellular carcinoma (HCC). However, small‐molecule inhibitors of LIF haven't been established. Here, we identified that LIF was remarkably overexpressed in HCC by multi‐omics approaches, indicating that inhibition of LIF would be a promising therapeutic strategy. Inhibiting LIF could suppress proliferation and metastasis by activating p38MAPK/p62‐modulated mitophagy. Interestingly, we found that the natural small‐molecule Cyclovirobuxine‐D (CVB‐D), was a new inhibitor of cytoplasmic LIF in HCC. We further validated LIF as a potential target of CVB‐D through biotin‐modified CVB‐D‐Probe utilizing mass spectrometry. Mechanistically, we showed that CVB‐D could bind to LIF at Val145, thereby inducing mitophagy, accompanied by cell cycle arrest and inhibition of invasion and migration. Moreover, we demonstrated that CVB‐D had a therapeutic potential by targeting LIF‐modulated mitophagy in patient‐derived xenograft (PDX) models, which would elucidate LIF as a druggable target and regulatory mechanisms and exploit CVB‐D as the novel small‐molecule inhibitor of LIF for future HCC drug discovery. |
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| ISSN: | 2688-2663 |