Protein kinases: The key contributors in pathogenesis and treatment of nonalcoholic fatty liver disease-derived hepatocellular carcinoma

Protein kinases (PKs), one of the largest protein families, can be further divided into different groups based on their substrate or structure and function. PKs are important signaling messengers in numerous life activities, including cell metabolism, proliferation, division, differentiation, senescence, death, and disease. Among PK-related diseases, nonalcoholic fatty liver disease (NAFLD) has been recognized as a major contributor to hepatocellular carcinoma (HCC) and liver transplantation. Unfortunately, NAFLD-derived HCC (NAFLD-HCC) has poor prognosis because it is typically accompanied by older age, multiple metabolic syndromes, obstacles in early-stage diagnosis, and limited licensed drugs for treatment. Accumulating evidence suggests that PKs are implicated in the pathogenic process of NAFLD-HCC, via aberrant metabolism, hypoxia, autophagy, hypoxia, gut microbiota dysbiosis, and/or immune cell rearrangement. The present review aims to summarize the latest research advances and emphasize the feasibility and effectiveness of therapeutic strategies that regulate the expression and activities of PKs. This might yield clinically significant effects and lead to the design of novel PK-targeting therapies. Furthermore, we discuss emerging PK-based strategies for the treatment of other malignant diseases similar to NAFLD-HCC.