Aspirin in hepatocellular carcinoma: is it an out-of-date or promising treatment?

Hepatocellular carcinoma (HCC) is one of the most aggressive human malignancies with a dismal survival rate. Few strategies can effectively prevent the occurrence of HCC. Although immunotherapy has significantly improved HCC-related survival in recent years, this systemic therapy is very expensive and lays a heavy burden on most HCC patients. Aspirin, which is currently one of the most widely used medications in analgesic and cardiovascular diseases, is reported to have anti-tumor effects on HCC. Most importantly, long-term administration of low-dose aspirin does not significantly increase the risk of gastrointestinal bleeding. Owing to its cost-effectiveness and wide use, aspirin can be easily applied as an HCC treatment and is affordable for a wide range of patients. Therefore, deeper understanding and more attention are needed to extend the frontline of aspirin's preventive and therapeutic potential into cancer research and management. In this review, we discuss the preventive effect of aspirin on HCC in the context of different etiological factors, including hepatitis B or hepatitis C virus infection, non-alcoholic fatty liver disease, and alcohol-associated liver disease. The therapeutic role of aspirin in resectable or unresectable HCC management is also discussed. Furthermore, the mechanisms underlying the anti-cancer effects of aspirin on HCC are fully reviewed and discussed in the following two aspects: the effect of aspirin on multi-oncogenic signaling pathways in HCC (e.g., AMPK, Wnt/β-catenin, NF-κB) and aspirin-mediated immunometabolic responses in liver diseases. These findings indicate aspirin is a promising agent for populations at risk and HCC patients to prevent or treat HCC.