Hepatocellular carcinoma (HCC)—the dominant form of liver cancer with no effective treatment strategies—has become the second leading cause of cancer-related death worldwide. Interestingly, almost all types of HCCs arise in the context of inflammation that is characterized by infiltration of immune cells to the liver where they produce inflammatory mediators to induce fibrosis/cirrhosis and eventually give rise to HCC. Therefore, understanding how inflammation is activated in the liver becomes important for developing effective anti-HCC therapies. Thanks to the close collaboration between clinical oncologists and bench scientists, we now know that activation of an immune sensor—called the NL...

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Hepatocellular carcinoma (HCC)—the dominant form of liver cancer with no effective treatment strategies—has become the second leading cause of cancer-related death worldwide. Interestingly, almost all types of HCCs arise in the context of inflammation that is characterized by infiltration of immune cells to the liver where they produce inflammatory mediators to induce fibrosis/cirrhosis and eventually give rise to HCC. Therefore, understanding how inflammation is activated in the liver becomes important for developing effective anti-HCC therapies. Thanks to the close collaboration between clinical oncologists and bench scientists, we now know that activation of an immune sensor—called the NLRP3 (Nod-like receptor pyrin domain containing 3) inflammasome—is responsible for initiating liver inflammation. However, how the NLRP3 inflammasome gets activated is still unclear, thus making it a hurdle for anti-HCC drug development. Our research group recently discovered that mitochondrion—the ‘powerplant’ of our cells—can also function as a ‘command center’ that decides whether the NLRP3 inflammasome is activated or not. Particularly, we found that a mitochondrial content—the mitochondrial DNA (mtDNA)—is the key driver for NLRP3 inflammasome activation. Importantly, we further identified a key switch, called CMPK2, that turns on mtDNA synthesis, thereby promoting the NLRP3 inflammasome activation. Because CMPK2 levels are strongly elevated in HCC from both humans and mice, we hypothesize that CMPK2 is required for liver inflammation and thereby promotes HCC development. In this proposal, we plan to utilize multiple cutting-edge experimental approaches to comprehensively and vigorously test the role of CMPK2 in HCC development. The research results gained from this study will pave the way for developing effective anti-HCC therapies (e.g. CMPK2 inhibitors).

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