Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is characterized by a high rate of metastasis and recurrence. Although lenvatinib is widely used as a first-line chemotherapy for advanced HCC, its clinical benefit is limited, owing to drug resistance. StAR-related lipid transfer protein 4 (STARD4), a protein regulated by the sterol-responsive element-binding protein 2 (SREBP-2), plays a crucial role in maintaining intracellular cholesterol homeostasis. However, its role and underlying mechanisms in HCC progression remain unclear.
This research, published in the Genes & Diseases journal by a team from Southern Medical University, explores the effects of STARD4 on the growth and resistance of HCC to lenvatinib and elucidates the potential role of epidermal growth factor receptor (EGFR) activation in mediating the effects of STARD4.

By examining 52 clinical samples from patients diagnosed with HCC, the research team identified significant up-regulation of STARD4 mRNA and protein levels in tumor tissues compared to adjacent normal tissues. Further analysis revealed a strong correlation between STARD4 expression and more aggressive clinicopathological features, suggesting that STARD4 could serve as a prognostic biomarker for HCC.

In vitro and in vivo studies demonstrated that STARD4 promoted HCC growth and hindered lenvatinib's anti-tumor effect, while STARD4 down-regulation exerted the opposite effects. Further investigation revealed that depletion of STARD4 increased cholesterol accumulation in the plasma membrane, resulting in reduced EGFR phosphorylation. Remarkably, cholesterol depletion decreased these effects, suggesting STARD4 promotes the activation of the EGFR/PI3K/AKT signaling pathway in HCC cells by regulating cholesterol homeostasis.

Notably, STARD4 and EGFR expression were significantly up-regulated in lenvatinib-resistant (LR) HCC cell lines. These cells demonstrated enhanced proliferation, migration, and invasion under lenvatinib treatment. Silencing STARD4 not only sensitized HCC cells to lenvatinib but also restored its anti-tumor efficacy in both in vitro and in vivo models. Interestingly, the EGFR inhibitor erlotinib suppressed the promotion of HCC progression by STARD4, reinforcing its role in activating the EGFR/PI3K/AKT pathway. In in vivo studies, STARD4 knockdown significantly inhibited tumor growth, and its combination with lenvatinib produced the strongest anti-tumor response, minimizing tumor progression.

In conclusion, this study demonstrates that STARD4 promotes the proliferation, metastasis, and lenvatinib resistance of HCC by modulating cholesterol homeostasis and subsequently activating the EGFR/PI3K/AKT pathway. These findings propose that STARD4 holds potential as a valuable molecular biomarker for predicting lenvatinib resistance and as a promising therapeutic target for HCC treatment.

Reference

Title of Original Paper: Targeting STARD4/EGFR axis inhibits growth and overcomes lenvatinib resistance in hepatocellular carcinoma

Journal: Genes & Diseases

Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101556

Funding Information:

Guangdong Basic and Applied Basic Research Foundation of China (No. 2023A1515012595, 2024A1515012743)
Nanfang Hospital Dean's Fund (No. 2022A010)
Wu Jieping Medical Foundation (No. 320.6750.2023-06-18)
Hospital Pharmacy Research Foundation of the Guangdong Liver Disease Association of China (No. 2023gdsgzbzd01)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus Cite Score: 8.4 | Impact Factor: 9.4

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