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Syntaxin-6 mediated autophagy confers lenvatinib resistance in hepatocellular carcinoma

Oncogene volume 44, pages 2025–2039 (2025)Cite this article

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Abstract

Lenvatinib is the first-line therapy for inoperable HCC. However, intrinsic and acquired drug resistance occurs during the treatment period. Autophagy is an adaptive response that favors tumor survival under stress. In the present study, we aim to reveal the unknown autophagic engagement in lenvatinib resistance. Lenvatinib-resistant HCC cell lines and xenograft mouse HCC models were established to identify the key regulator of lenvatinib resistance in HCC. By in vitro functional restoration assays and autophagic flux detection, we demonstrated that the Syntaxin-6 (STX6) -mediated autophagy induced lenvatinib resistance of HCC cells. Mechanistically, Co-immunoprecipitation assay and mass spectrometry indicated that the interactions of STX6 with Beclin1, VTI1A, and VAMP3 facilitated autophagy, leading to the lenvatinib resistance. Additionally, STX6 enhanced the ability of proliferation, migration, and invasion of HCC in vitro and in vivo. Clinically, STX6 expression was significantly elevated in HCC tissues compared to it in para-tumor tissues. High STX6 expression predicted poor outcomes for patients following resection. Moreover, high expression of STX6 displayed low preventive efficacy of lenvatinib as a postoperative adjuvant treatment for HCC patients with a high risk of recurrence. Collectively, we identified that STX6-mediated autophagy plays a crucial role in lenvatinib resistance in HCC, providing a potential therapeutic target to overcome lenvatinib resistance for HCC patients.

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Fig. 1: STX6 confers lenvatinib resistance of HCC.
Fig. 2: Lenvatinib induces autophagy in HCC cells.
Fig. 3: Lenvatinib-induced autophagy is mediated by STX6.
Fig. 4: Interaction of STX6 with Beclin1, VTI1A, and VAMP3 facilitates autophagy to confer lenvatinib resistance.
Fig. 5: STX6 promotes HCC progression.
Fig. 6: High expression of STX6 predicts poor prognosis of patients with HCC and resistance to lenvatinib adjuvant treatment.

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Data availability

The RNA sequencing data of lenvatinib-resistant and their corresponding parental HCC cells have been publicly deposited at Gene Expression Omnibus (GEO accession number: GSE285575). All data are contained within the article. Requests for reagents should be addressed to Shao-Qiang Li ([email protected]).

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Funding

This work was supported by the National Natural Science Foundation of China (No.82072663) and the China Postdoctoral Science Foundation (No.2024M763772).

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  1. These authors contributed equally: Guo-Pei Zhang, Ze-Bing Song, De-Hua Chen.

Authors and Affiliations

  1. Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

    Guo-Pei Zhang, Ze-Bing Song, De-Hua Chen, Yang Yu, Fei-Feng Wu, Ming Kuang & Shao-Qiang Li

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Contributions

SQL and GPZ conceived of the study. ZBS, GPZ, and DHC were involved in data acquisition and interpretation. YY and FFW contributed to the statistical analysis. GPZ and ZBS wrote the original manuscript. MK reviewed the manuscript and patient management. SQL supervised the study and reviewed the manuscript. All authors read and approved the manuscript.

Corresponding author

Correspondence to Shao-Qiang Li.

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Competing interests

The authors declared no competing interests.

Ethical approval

All animal experiments were approved by the Institutional Care and Animal Use Committee of the First Affiliated Hospital of Sun Yat-sen University (Approval No [2021]308). We have obtained patients’ consent for publication. All human specimens were approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University (Approval No [2021]388). All methods were performed in accordance with the relevant guidelines and regulations.

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Zhang, GP., Song, ZB., Chen, DH. et al. Syntaxin-6 mediated autophagy confers lenvatinib resistance in hepatocellular carcinoma. Oncogene 44, 2025–2039 (2025). https://doi.org/10.1038/s41388-025-03371-7

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