Study Finds VPS72 Is Overactive in Patients With Hepatocellular Carcinoma

Study findings published in Advanced Science show that a novel regulatory axis appears to be linked to dysregulated lipid metabolism with hepatocellular carcinoma (HCC) progression, highlighting potential epigenetic and metabolic targets for therapeutic intervention. Specifically, the study authors point to VPS72 as an epigenetic regulator of lipid metabolism within HCC and note that it can be crucial between the development of cancer and lipid homeostasis.¹

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HCC is the most prevalent type of primary liver cancer in adults. According to the study authors, it represents the sixth leading cause of cancer-related mortality in the US and was the fourth most commonly diagnosed cancer worldwide in 2022. The dysregulation of lipid metabolism in hepatocytes is central to its pathogenesis, leading to abnormal lipid accumulation. Major risk factors of HCC are metabolic dysfunction-associated steatohepatitis (MASH) and viral hepatitis.^1,2

MASH, formerly known as nonalcoholic steatohepatitis, is a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD) that often accompanies various metabolic diseases (eg, obesity and diabetes). It is the inflammation of the liver caused by excess fat cells, and this chronic inflammation eventually causes progressive liver damage. Additionally, it can also be associated with high blood lipids and high blood sugar. The Cleveland Clinic estimates that MASLD affects up to 25% of US adults, and among that population, about 20% have MASH. If left untreated, the disease can lead to HCC.²

Based on prior evidence that linked VPS72 to HCC progression, the investigators examined TCGA Liver Hepatocellular Carcinoma (LIHC) patient data to explore any associations between VPS72 copy number, expression levels, and patient survival outcomes. The investigators observed there was a significant positive correlation between VPS72 copy number and its expression, which suggests that the early oncogenic amplification of VPS72 may push its overexpression, contributing to the development of HCC. Additionally, the VPS72 gene was found to be present in extra copies in over half of the evaluated samples, indicating that gains may play a pivotal role in HCC pathogenesis.¹

Further, VPS72 expression was noticeably higher in tumor tissues compared with noncancerous controls, and survival analysis revealed a strong association between elevated VPS72 expression and reduced overall survival. Additionally, by integrating RNA-Seq, ChIP-Seq, ATAC-seq, and experimental validation, the investigators found that VPS72 overexpression activates mTORC1 signaling, therefore promoting lipid synthesis and driving HCC progression. They also determined that VPS72 modulates the epigenetic landscape by enhancing DNA methylation at the ATF3 promoter, resulting in ATF3 repression and subsequent activation of mTORC1.¹

Of note, the VPS72-ATF3-mTORC1-lipogenesis axis identified not only emphasizes an oncogenic potential of VPS72 but also establishes a new model for understanding the epigenetic regulation of metabolic reprogramming in HCC. Because regulating diverse metabolic pathways—including gluconeogenesis and adipocyte browning—is the central role of ATF3, abnormal VPS72 expression may have broader consequences beyond lipid metabolism, wrote the authors.¹

The authors emphasized that their findings also raise the possibility of therapeutic targeting of VPS72 or its interaction with H2A.Z. Disrupting this axis could offer a novel strategy to inhibit lipid biosynthesis and tumor growth. They called on future studies to clarify additional pathways regulated by VPS72 and explore its potential as a therapeutic target across different cancer types.¹

“Our research shows that the gene VPS72 plays 2 key roles in liver cancer (HCC): it affects both how genes are controlled and how fat metabolism goes wrong. The findings help explain how liver cancer develops and suggest new ways to treat cancers driven by abnormal fat metabolism,” corresponding author Jiangwen Zhang, PhD, professor at the School of Biological Sciences at the University of Hong Kong, said in a news release.³

REFERENCES

1. Zhang Q, Huang Y, Tong Y, Ng KTC, Zhang J. Copy Number Gains of VPS72 Drive De Novo Lipogenesis and Hepatocarcinogenesis via ATF3/mTORC1/SREBP1 Axis. Adv. Sci. 2025, 12, 2411368. doi:10.1002/advs.202411368

2. McGovern G. Engineered Extracellular Vesicles May Be a New Approach to Treating MASH. Pharmacy Times. May 2, 2025. Accessed June 5, 2025. https://www.pharmacytimes.com/view/engineered-extracellular-vesicles-may-be-a-new-approach-to-treating-mash

3. The University of Hong Kong. HKU biologists uncover how a genetic player fuels liver cancer by disrupting fat metabolism. News release. June 3, 2025. Accessed June 5, 2025. https://www.eurekalert.org/news-releases/1086257