Tumor Necrosis Factor-Alpha and Adiponectin in Nonalcoholic Fatty Liver Disease-Associated Hepatocellular Carcinoma

Simple Summary The prevalence of nonalcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is rapidly increasing, following the growing prevalence of NAFLD. The pathophysiological mechanisms of NAFLD-associated HCC are not fully elucidated. Emerging preclinical and limited clinical studies suggest that tumor necrosis factor-alpha (TNF-alpha) and adiponectin may contribute to the progression from NAFLD to HCC. This may render both TNF-alpha and adiponectin as appealing therapeutic targets in the setting of NAFLD-associated HCC, for which systemic immunotherapy, i.e., immune checkpoint inhibitors (ICIs), seems to be less effective compared to HCC of other etiologies. Therefore, anti-TNF biologics and/or adiponectin analogs or medications that increase endogenous adiponectin may be investigated combined with ICIs in the treatment of NAFLD-associated HCC.Abstract Nonalcoholic fatty liver disease (NAFLD) is emerging as an important risk factor for hepatocellular carcinoma (HCC), whose prevalence is rising. Although the mechanisms of progression from NAFLD to HCC are not fully elucidated, tumor necrosis factor-alpha (TNF-alpha) and adiponectin, as well as their interplay, which seems to be antagonistic, may contribute to the pathophysiology of NAFLD-associated HCC. TNF-alpha initially aims to protect against hepatocarcinogenesis, but during the progression of NAFLD, TNF-alpha is increased, thus probably inducing hepatocarcinogenesis in the long-term, when NAFLD is not resolved. On the other hand, adiponectin, which is expected to exert anti-tumorigenic effects, is decreased during the progression of the disease, a trend that may favor hepatocarcinogenesis, but is paradoxically increased at end stage disease, i.e., cirrhosis and HCC. These observations render TNF-alpha and adiponectin as potentially diagnostic biomarkers and appealing therapeutic targets in the setting of NAFLD-associated HCC, possibly in combination with systematic therapy. In this regard, combination strategy, including immune checkpoint inhibitors (ICIs) with anti-TNF biologics and/or adiponectin analogs or medications that increase endogenous adiponectin, may warrant investigation against NAFLD-associated HCC. This review aims to summarize evidence on the association between TNF-alpha and adiponectin with NAFLD-associated HCC, based on experimental and clinical studies, and to discuss relevant potential therapeutic considerations.