Resistance by Inhibiting the STAT3/SLC25A27 Pathway and Promoting Ferroptosis in Hepatocellular Carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Drug Resistance Mechanisms

Background:

• Lenvatinib is a first-line treatment for advanced hepatocellular carcinoma (HCC).
• Therapeutic efficacy of lenvatinib is often limited by the development of resistance.
• Understanding lenvatinib resistance mechanisms is crucial for improving HCC treatment outcomes.

Purpose of the Study:

• To investigate the molecular pathways contributing to lenvatinib resistance in HCC.
• To identify potential therapeutic targets for overcoming lenvatinib resistance.
• To evaluate the efficacy of combining artesunate with lenvatinib in HCC.

Main Methods:

• RNA sequencing (RNA-seq) to identify differentially expressed genes in lenvatinib-resistant HCC cells.
• Quantitative real-time PCR (qRT-PCR), western blot, and immunohistochemistry (IHC) to validate SLC25A27 expression.
• Cell viability (CCK-8), proliferation (colony formation), ROS, mitochondrial morphology (TEM), MDA, GSH/GSSG ratio, and MMP assays to assess cellular functions.
• Gain- and loss-of-function experiments to determine the role of SLC25A27.
• Dual-luciferase reporter assays to confirm STAT3-mediated SLC25A27 transcription.

Main Results:

• Solute carrier family 25 member 27 (SLC25A27) was significantly upregulated in lenvatinib-resistant HCC cells and tissues.
• SLC25A27 overexpression promoted HCC cell survival, proliferation, and lenvatinib resistance.
• SLC25A27 inhibited the ferroptosis pathway by activating the SLC7A11/GPX4 axis.
• Signal transducer and activator of transcription 3 (STAT3) was identified as a key transcriptional activator of SLC25A27.
• Artesunate treatment promoted ferroptosis by inhibiting the STAT3/SLC25A27/SLC7A11/GPX4 axis in vitro and in vivo.

Conclusions:

• SLC25A27 plays a critical role in promoting lenvatinib resistance in HCC by suppressing ferroptosis.
• The STAT3/SLC25A27/SLC7A11/GPX4 signaling axis is a key pathway mediating lenvatinib resistance.
• Combination therapy with artesunate and lenvatinib significantly enhances anti-HCC effects by overcoming lenvatinib resistance.
• Targeting the STAT3/SLC25A27 pathway presents a promising strategy for managing advanced HCC.