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LAMTOR5 promotes hepatoma growth in mice by disrupting LC3-p62-mediated autophagy and preventing p62 proteasome degradation

Acta Pharmacologica Sinica volume 47, pages 1042–1057 (2026)Cite this article

Abstract

In the etiology of cancer, p62 is a well-known autophagic receptor and signaling adapter. High p62 expression is known to accelerate hepatocellular carcinoma (HCC) growth by activating various downstream signaling pathways. In this study, we investigated the activity of elevated p62 and its associated regulatory mechanisms during HCC progression. By conducting immunohistochemical staining on a human liver tissue microarray including 10 liver cancer tissues and 10 paracancerous tissues, we found that the expression levels of p62 and oncoprotein LAMTOR5 were markedly increased in HCC tissues compared with noncancerous tissues; LAMTOR5 was positively associated with p62 expression, and high LAMTOR5 or p62 expression predicted reduced overall and release-free survival. Transcriptomic analysis revealed that LAMTOR5 overexpression inhibited autophagy in HepG2 cells. We demonstrated that LAMTOR5 interacted with the LC3-interacting region domain of p62 and inhibited autophagy caused by the binding of p62 to LC3, thereby leading to the accumulation of p62 protein in HCC. Moreover, LAMTOR5 blocked p62 ubiquitination-mediated proteasome degradation, which increased the stability of p62. Functionally, p62 overexpression reversed LAMTOR5 deficiency-reduced hepatoma cell proliferation in vitro and in vivo. Lenvatinib, a multi-receptor tyrosine kinase inhibitor, significantly suppressed HCC growth in vitro and in vivo by downregulating LAMTOR5 and p62 expression. We conclude that LAMTOR5-mediated p62 stabilization is a novel HCC growth mechanism, targeting this axis as a promising therapeutic strategy.

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Fig. 1: LAMTOR5 is positively associated with p62 expression in human liver tissue.
Fig. 2: LAMTOR5 attenuates autophagic flux in hepatoma cells.
Fig. 3: Binding between LAMTOR5 and p62 inhibits autophagy.
Fig. 4: LAMTOR5 deficiency inhibits p62 protein stability and disrupts autophagy inhibition-mediated proliferation of hepatoma cells.
Fig. 5: P62 reverses the LAMTOR5 deficiency-induced reduction in hepatoma cell proliferation in vitro and in vivo.
Fig. 6: P62 deficiency interferes LAMTOR5-induced signaling pathways in hepatoma cells.
Fig. 7: LV suppresses hepatoma growth by targeting LAMTOR5 and p62.

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Acknowledgements

We thank Zhuo-wei Hu (Chinese Academy of Medical Sciences, Peking Union Medical College) for Flag-tagged p62 plasmids and Xiao-bo Qiu (Beijing Normal University) for GFP-RFP-LC3 plasmids. This work was supported by the National Natural Scientific Foundation of China [82202950, 82072943, and 82072929].

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  1. These authors contributed equally: Fei-fei Xu, Hui-min Sun, Yuan Liu

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Nankai University, Tianjin, 300071, China

    Fei-fei Xu, Hui-min Sun, Yuan Liu, Kai Ye, Zhi-yu Liu, Xue-li Fu, Wei-ying Zhang & Li-hong Ye

  2. Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China

    Fei-fei Xu

  3. Liaoning Provincial Key Laboratory of Clinical Oncology Metabonomics, Institute of Clinical Bioinformatics, Cancer Center of Jinzhou Medical University, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, China

    Zhi-tu Zhu

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Contributions

FFX, ZTZ, WYZ, and LHY designed the research; FFX, HMS, YL, KY, ZYL, and XLF conducted experiments; FFX, HMS, and YL analyzed data and wrote the main paper; ZTZ, WYZ, and LHY revised the paper. All authors read and provided approval for the final paper.

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Correspondence to Zhi-tu Zhu, Wei-ying Zhang or Li-hong Ye.

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Xu, Ff., Sun, Hm., Liu, Y. et al. LAMTOR5 promotes hepatoma growth in mice by disrupting LC3-p62-mediated autophagy and preventing p62 proteasome degradation. Acta Pharmacol Sin 47, 1042–1057 (2026). https://doi.org/10.1038/s41401-025-01687-4

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