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Unveiling EMC6 as a novel pathogenic determinant in hepatocellular carcinoma: orchestration of lipid metabolism through regulation of lipid droplet-associated enzyme HSD17B13

Oncogene volume 45, pages 322–338 (2026)Cite this article

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Abstract

The endoplasmic reticulum (ER) membrane protein complex (EMC) is an ER multiprotein complex that affects a wide range of pathophysiological processes. Recently, the function of EMC6, a subunit of EMC, has been attracting attention for its role in cancers. However, research on EMC6 in the context of hepatocellular carcinoma (HCC) remains unknown. Here, we first observed the decreased EMC6 expression in human HCC tissues, and diminished expression level of EMC6 was associated with poor prognosis of HCC patients. In parallel, the knockdown of EMC6 promoted tumor progression both in HCC cell lines and in tumor-cell bearing nude mice. To delineate the in vivo roles of EMC6, we generated a hepatocyte-specific knockout of Emc6 (Emc6f/f;Alb-Cre, named Emc6 LKO) using a floxed Emc6 line. Emc6 LKO mice exhibited progressive liver dysfunction, fibrosis and spontaneous carcinogenesis phenotypes. Significant lipid metabolic disorder in the Emc6 LKO liver was revealed by combined metabolomic and proteomic analysis. Moreover, drastic elevation of 17β-Hydroxysteroid dehydrogenase type 13 (HSD17B13), a lipid droplet-associated enzyme, was identified to be involved in the process of EMC6-induced lipid metabolic disorder and HCC progression. Inhibition of HSD17B13 by a Pharmacological inhibitor BI-3231 effectively mitigated EMC6-driven HCC progression in vitro and in vivo. Taken together, these results unveiled a novel regulatory mechanism of EMC in HCC progression through lipid metabolism and may provide a new biomarker and therapeutic target for HCC.

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Fig. 1: EMC6 expression in HCC tissues and adjacent tissues in multiple cohorts.
Fig. 2: EMC6 knockdown promotes tumor progression in vitro and in vivo.
Fig. 3: Hepatic dysfunction and tumorigenesis in Emc6 LKO mice.
Fig. 4: Metabolic and proteomic changes in Emc6-deficient liver tissues.
Fig. 5: Association of HSD17B13 with EMC6.
Fig. 6: HSD17B13 inhibition suppresses HCC progression.

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Data availability

All data are available in the main text or the supplementary materials. Metabolomics data can be found under National Genomics Data Center accession number OMIX010094. Proteomics data can be found under ProteomeXchange accession number PXD067920 (hosting repository: iProX, project ID IPX0013248000).

Code availability

Code used during the study is available from the corresponding authors or first authors by request.

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Acknowledgements

We thank all the patients who agreed to provide their tissue for research purposes.

Funding

This work was supported by the National Natural Science Foundation of China (No. 81970825 to YuZ); the Department of Science and Technology of Sichuan Province (No. 2023ZYD0172 to XZ, No. 2024NSFSC0744 to SZ, and No. 2022JDJQ0062 to YuZ); the Chengdu Science and Technology Program (No. 2024-YF05-01868-SN); the Sichuan Returned Overseas Talent Funding (YuZ and SZ); the Human Resources and Social Security Department of Sichuan Province (2021) and research grant from Jinfeng Laboratory (JFLKYXM202403AZ-101).

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  1. These authors contributed equally: Yun Zhang, Chanyu Xiong, Zhilin Jiang.

Authors and Affiliations

  1. Genetic Diseases Key Laboratory of Sichuan Province, Medical Genetics and Rare Diseases Center, Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China

    Yun Zhang, Chanyu Xiong, Zhilin Jiang, Xiao Wang, Zihao Wang, Junyao Chen, Qiong Li, Yangyang Luo, Xianjun Zhu & Yu Zhou

  2. Organ Transplant Center, Sichuan Provincial Key Laboratory for Clinical Immunology Translational Medicine, School of Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China

    Yun Zhang & Shikai Zhu

  3. Department of Pathology, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China

    Xudan Yang

  4. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    Chen Chu

  5. Sichuan-Chongqing Joint Key Laboratory for Pathology and Laboratory Medicine, Jinfeng Laboratory, Chongqing, China

    Xianjun Zhu

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Contributions

YuZ, XZ and SZ was responsible for Conceptualization, Funding acquisition, Project administration, Supervision, Writing – review & editing. YunZ, CX and ZJ was responsible for Investigation, Visualization, and Writing – original draft. YL contributed to Methodology. XW, ZW, JC, XY contributed to Investigation. QL contributed to Visualization. CC contributed to Writing – review & editing.

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Correspondence to Shikai Zhu, Xianjun Zhu or Yu Zhou.

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Zhang, Y., Xiong, C., Jiang, Z. et al. Unveiling EMC6 as a novel pathogenic determinant in hepatocellular carcinoma: orchestration of lipid metabolism through regulation of lipid droplet-associated enzyme HSD17B13. Oncogene 45, 322–338 (2026). https://doi.org/10.1038/s41388-025-03649-w

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