Don’t Judge a Book by Its Cover: The Role of Statins in Liver Cancer

Abstract

Statins, which are inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, are an effective pharmacological tool for lowering blood cholesterol levels. This property makes statins one of the most popular drugs used primarily to prevent cardiovascular diseases, where hyperlipidemia is a significant risk factor that increases mortality. Nevertheless, studies conducted mainly in the last decade have shown that statins might prevent and treat liver cancer, one of the leading causes of cancer-related mortality worldwide. This narrative review summarizes the scientific achievements to date regarding the role of statins in liver tumors. Molecular biology tools have revealed that cell growth and proliferation can be inhibited by statins, which further inhibit angiogenesis. Clinical studies, supported by meta-analysis, confirm that statins are highly effective in preventing and treating hepatocellular carcinoma and cholangiocarcinoma. However, this effect may depend on the statin’s type and dose, and more clinical trials are required to evaluate clinical effects. Moreover, their potential hepatotoxicity is a significant caveat for using statins in clinical practice. Nevertheless, this group of drugs, initially developed to prevent cardiovascular diseases, is now a key candidate in hepato-oncology patient management. The description of new drug-statin-like structures, e.g., with low toxicity to liver cells, may bring another clinically significant improvement to current cancer therapies.

Association between blood lipid levels and the risk of liver cancer: a systematic review and meta-analysis

“…The primary mechanism of action of statins involves competitively inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), thereby lowering lipid levels. Currently, the proposed mechanism by which statins prevent liver cancer involves modulating the tumor microenvironment and autophagic responses [ 76 ]. In this study, the reduction in lipid levels was linked to an increased risk of liver cancer, which seems contradictory to the protective role of statins against liver cancer.…”

The Impact of Statins on the Survival of Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib or Lenvatinib

“…This study is noteworthy because it is the first to investigate the potential survival benefits of statins in patients with advanced HCC treated with TKIs using nationwide and multicenter data from the HIRA in Korea. The study begins by acknowledging that statins have previously been associated with a reduced risk of HCC development in patients with chronic liver disease and a decreased risk of tumor recurrence after curative resection in early-stage HCC [10][11][12][13][14][15][16][17][18]. However, statin use is often limited due to safety concerns, particularly in patients with a cirrhotic liver.…”

“…Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA), and they also have potential chemopreventive and cytotoxic effects on cancer cells in different types of cancers, primarily through the inhibition of the mevalonate pathway, independent of their lipid-lowering effect [7][8][9][10]. Statin use may be associated with a lower risk of HCC development in patients with hepatitis B or C infection and diabetes mellitus (DM) [11][12][13][14][15][16].…”

Non-Alcoholic Fatty Liver Disease and the Risk of Future Hepatocarcinoma

“…In patients with NAFLD, statins have shown promise in reducing the risk of hepatocarcinoma. The ability of statins to reduce inflammation in the liver and inhibit the proliferation of liver cancer cells; therefore, they may be an effective treatment option for hepatocarcinoma in patients with NAFLD (36,37).…”