Protein Linked to Cell Death May Also Drive Liver Cancer

OKLAHOMA CITY – New research from the University of Oklahoma identifies a protein in liver cells that appears to help drive the development of liver cancer associated with obesity-related fatty liver disease. The finding, published in Hepatology, points to the protein as a potential new therapeutic target for liver cancer.

The protein, MLKL (mixed lineage kinase domain-like protein), is best known for its role in necroptosis, a form of cell death. In this study, MLKL levels increased in mice fed a Western-style (high-fat) diet. However, rather than causing liver cell death, MLKL appears to reduce the function of mitochondria, the structures inside cells that produce energy, and promote tumor development in the liver. When MLKL was removed from liver cells in mice, fewer and smaller liver tumors developed.

“This finding was very surprising because it reveals a new role for MLKL, and it suggests that MLKL could be a therapeutic target for hepatocellular carcinoma, a primary form of liver cancer. We are excited to continue investigating whether targeting this protein could slow or prevent tumor growth,” said senior author Deepa Sathyaseelan, Ph.D., associate professor of biochemistry and physiology in the OU College of Medicine. She is also a member of OU Health Stephenson Cancer Center and OU Health Harold Hamm Diabetes Center.

The mechanism by which MLKL promotes tumor development involves another protein, MFN2 (mitofusin 2), which helps maintain healthy mitochondria. When MLKL increases in response to a high-fat diet, MFN2 decreases, thereby impairing mitochondrial function. In the absence of MLKL, MFN2 returns, improving mitochondrial function and leading to reduced tumor growth.

“Research has already shown us that mitochondrial dysfunction is a key driver for several liver diseases, including liver cancer,” Sathyaseelan said. “Our research identifies a mechanism by which that dysfunction occurs.”

Another surprising aspect of the research is that, even though the mice had fewer and smaller tumors when MLKL was absent, removing MLKL did not reduce fatty liver, liver inflammation, fibrosis or liver injury.

“Traditionally, we have considered liver cancer a progressive disease,” she said. “What we expected to see (with the removal of MLKL) was a reduction in fatty liver, a reduction in fibrosis and, eventually, a reduction in liver tumors. But that’s not what we found. It tells us that MLKL is regulating tumor development through a completely different pathway. That means we may have the potential to directly target liver cancer, which is good news because it is often not discovered until its later stages.”

In addition to experiments in mice and laboratory-grown liver cancer cells, Sathyaseelan’s team analyzed human liver cancer data sets and tumor samples. They found that tumors with higher levels of MLKL were associated with poorer overall survival.

Sathyaseelan and her team plan to continue studying MLKL as a potential therapeutic target, including investigating MLKL inhibitors and whether they could be combined with existing cancer treatments. They also plan to study whether MLKL can serve as a biomarker for liver cancer.

“Nearly 30% of the U.S. adult population has fatty liver disease,” she said. “For people who progress to liver cancer, the five-year overall survival is approximately 22%, and current therapies are not very effective. In years past, liver cancer was primarily caused by hepatitis B or C infections or chronic alcoholism. Now fatty liver disease is a major contributor. That’s why we need to understand the basic mechanism by which a fatty liver progresses to liver cancer.”

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About the project

The paper, “Hepatocyte MLKL drives obesity-driven hepatocellular carcinoma progression via mitochondrial dysfunction independent of necroptosis in MASLD,” is at https://pubmed.ncbi.nlm.nih.gov/42549799/. Collaborators include researchers at the OU Health Stephenson Cancer Center and the Oklahoma Medical Research Foundation. The research was supported by the National Institutes of Health, the Oklahoma Center for Adult Stem Cell Research, and a team science grant from the OU Health Harold Hamm Diabetes Center and OU Health Stephenson Cancer Center. This project was also supported by Oklahoma's Tobacco Settlement Endowment Trust (TSET), a primary funder of the Stephenson Cancer Center and TSET Health Promotion Research Center at the University of Oklahoma and by the Oklahoma Shared Clinical and Translational Resources through an Institutional Development Award from the National Institute of General Medical Sciences (grant no. U54GM104938).

About the University of Oklahoma

Founded in 1890, the University of Oklahoma is a public research university with campuses in Norman, Oklahoma City and Tulsa. As the state’s flagship university, OU serves the educational, cultural, economic and healthcare needs of the state, region and nation. In Oklahoma City, the OU Health Campus is one of the nation’s few academic health centers with seven health profession colleges located on the same campus. The OU Health Campus serves approximately 4,000 students in more than 70 undergraduate and graduate degree programs spanning Oklahoma City and Tulsa and is the leading research institution in Oklahoma. For more information about the OU Health Campus, visit www.ouhsc.edu.