Statin-Linked GGPP-Rho-YAP Pathway Identified in Cells Around Liver Tumors

Researchers at UCLA have identified a signaling pathway in cells surrounding fatty liver disease–related tumors that may help explain why statins, widely used cholesterol-lowering drugs, have been associated in previous studies with a lower risk of liver cancer. The study, published in Hepatology Communications, focused on hepatic stellate cells, which normally help maintain the liver’s structural framework but can alter their behavior in response to chronic injury. The team found that a specific population of these cells accumulates in the tissue surrounding tumors linked to metabolic dysfunction-associated steatotic liver disease, or MASLD, and shows heightened activity of a signaling pathway involving the protein YAP, a regulator of tissue remodeling and other cellular processes. The researchers also identified a potential mechanism through which statins may suppress this activity.

MASLD is the most common cause of chronic liver disease and has become an increasingly important risk factor for hepatocellular carcinoma, the most common type of primary liver cancer. Unlike many other causes of this cancer, MASLD-related hepatocellular carcinoma can develop even in people who do not have cirrhosis. Hepatic stellate cells, best known for their role in liver scarring, have increasingly been recognized by researchers as a heterogeneous population, with different subgroups exerting different effects on the liver and on the environment surrounding tumors. Statins, meanwhile, have been associated in earlier studies with a lower risk of both cirrhosis and liver cancer, but the biological mechanisms behind these associations have not been fully understood.

To map the cell populations involved, the researchers analyzed human liver tissue from patients with MASLD-related hepatocellular carcinoma who underwent liver resection or transplantation at UCLA. Using single-nucleus RNA sequencing, they identified distinct populations of hepatic stellate cells and examined their gene activity. Spatial imaging techniques then allowed them to determine where these cells and YAP-related genes were located relative to the tumors, revealing the accumulation of an activated stellate cell population in the peritumoral tissue. The team then conducted laboratory experiments using human hepatic stellate cells treated with statins, measuring changes in YAP activity, Rho GTPase signaling, and levels of geranylgeranyl pyrophosphate, or GGPP, a molecule that helps activate Rho GTPases, proteins involved in regulating a cell’s internal structure and signaling.

The experiments showed that statins reduced GGPP levels, which changed the structure of the stellate cells and caused YAP to remain outside the cell nucleus. With YAP excluded from the nucleus, its ability to activate genes involved in tissue remodeling and other cellular processes was diminished. When the researchers restored GGPP levels in the treated cells, the effects of the statins were reversed, providing evidence that the GGPP-Rho-YAP pathway plays an important role in how these drugs act on hepatic stellate cells. By manipulating GGPP levels and Rho signaling directly, the team was able to probe the contribution of each step in this chain, linking a metabolic intermediate to cytoskeletal signaling and ultimately to nuclear gene regulation.

The analysis of patient tissue also revealed increased expression of GGPS1, an enzyme that helps produce GGPP, in liver cells near the tumors. This observation raises the possibility that tumor cells may produce GGPP that influences nearby stellate cells, potentially sustaining the activated YAP state observed around the tumors. The researchers emphasized, however, that further studies are needed to determine whether this tumor-to-stellate-cell interaction actually occurs in patients. The findings point to the GGPP-Rho-YAP pathway as a potential area for future research into liver cancer prevention, but additional work is needed to establish whether altering this pathway can change the behavior of hepatic stellate cells or the environment surrounding liver tumors, and whether it could ultimately be targeted to reduce cancer development or progression.

The study’s authors were careful to note the limits of what the results demonstrate. The research does not show that statins can prevent or treat liver cancer, and the findings do not change how these medications should be used in patients. Instead, the work provides a starting point for understanding the biological effects of statins beyond their cholesterol-lowering action and for investigating whether those effects could be harnessed for cancer prevention in the future. “Our study provides several new insights into hepatocellular carcinoma, including a more detailed understanding of the different populations of hepatic stellate cells, which play a key role in the development of liver fibrosis and cirrhosis,” said senior author Dr. Jihane Benhammou, associate professor of medicine and digestive diseases at the David Geffen School of Medicine at UCLA and investigator at the UCLA Health Jonsson Comprehensive Cancer Center. “We also provide new insight into how statins may have chemopreventive effects through pathways that are independent of their cholesterol-lowering effects.” The study was completed through the Comprehensive Liver Research Center at UCLA, with postdoctoral fellow Courtney Labrecque as first author.

Subject of Research: A GGPP-Rho-YAP signaling pathway in hepatic stellate cells surrounding MASLD-related liver tumors and its potential suppression by statins

Article Title: Scientists uncover how cells surrounding primary liver tumors may help fuel cancer

Article References: Scientists uncover how cells surrounding primary liver tumors may help fuel cancer. Original publication (Bibliographic details unavailable.)

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Keywords: hepatocellular carcinoma, MASLD, hepatic stellate cells, statins, YAP signaling, GGPP, Rho GTPases, single-nucleus RNA sequencing, liver cancer prevention, Hepatology Communications, UCLA, fatty liver disease