Sorafenib-induced macrophage extracellular traps via ARHGDIG/IL4/PADI4 axis confer drug resistance through inhibiting ferroptosis in hepatocellular carcinoma
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View abstract on PubMed
Summary
This summary is machine-generated.Sorafenib resistance in liver cancer is linked to macrophage extracellular traps (METs). Targeting the IL4/PADI4/METs pathway can overcome this resistance by restoring cancer cell ferroptosis.
Area Of Science
- Oncology
- Immunology
- Biochemistry
Background
- Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide.
- Sorafenib is a first-line treatment for HCC, but drug resistance is a significant clinical challenge.
- The mechanisms underlying sorafenib resistance in HCC remain incompletely understood.
Purpose Of The Study
- To investigate the role of macrophage extracellular traps (METs) in mediating crosstalk between macrophages and tumor cells contributing to sorafenib resistance in HCC.
- To elucidate the molecular mechanisms involving IL4, PADI4, and METs in the development of sorafenib resistance.
- To explore therapeutic strategies targeting the identified pathway to overcome sorafenib resistance.
Main Methods
- Immunofluorescence and ELISA were used to detect METs and measure related factors in HCC tissues.
- Quantitative real-time PCR (qRT-PCR) and Western Blot assays were employed to analyze gene and protein expression levels.
- Cell viability, migration, and ferroptosis assays were performed to assess cellular responses.
- In vivo experiments in HCC mouse models were conducted to evaluate the therapeutic efficacy of targeting the IL4/PADI4/METs axis.
Main Results
- Sorafenib induced MET formation in M2 macrophages, which was associated with increased IL4 secretion by HCC cells.
- METs were found to inhibit the ferroptosis of HCC cells, contributing to sorafenib resistance.
- DNase I treatment to clear METs or IL4 neutralization significantly improved sorafenib efficacy in HCC models.
- Inhibition of PADI4, an enzyme upregulated by IL4 in M2 macrophages, also reversed sorafenib resistance.
Conclusions
- Sorafenib-induced METs play a critical role in promoting sorafenib resistance in HCC by suppressing tumor cell ferroptosis.
- The IL4/PADI4/METs axis represents a novel therapeutic target for overcoming sorafenib resistance in HCC.
- Targeting this axis offers a promising strategy to enhance the effectiveness of sorafenib treatment in liver cancer patients.
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