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

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-α (TNF-α) and adiponectin, as well as their interplay, which seems to be antagonistic, may contribute to the pathophysiology of NAFLD-associated HCC. TNF-α initially aims to protect against hepatocarcinogenesis, but during the progression of NAFLD, TNF-α 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-α 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-α and adiponectin with NAFLD-associated HCC, based on experimental and clinical studies, and to discuss relevant potential therapeutic considerations.

Namodenoson at the Crossroad of Metabolic Dysfunction-Associated Steatohepatitis and Hepatocellular Carcinoma

“…These preclinical findings were consistent with results from the phase 2B study of namodenoson in MASLD/MASH, where increased levels of adiponectin in the serum of patients treated with namodenoson were recorded [15]. Moreover, these findings are also in line with other studies showing that increased adiponectin levels are associated with marked improvement in liver diseases such as alcoholic liver disease (ALD), hepatic fibrosis, MASLD/MASH, and HCC [51][52][53][54]. Adiponectin levels in the plasma are lower in obese individuals vs. those with normal weight, and obesity has been associated in epidemiologic studies with many common cancers, with the strongest evidence for digestive system cancers, including liver cancer [55].…”

“…Adiponectin levels in the plasma are lower in obese individuals vs. those with normal weight, and obesity has been associated in epidemiologic studies with many common cancers, with the strongest evidence for digestive system cancers, including liver cancer [55]. In vitro and in vivo evidence also support the association of lower levels of adiponectin with tumor-promoting pathways and higher levels of adiponectin with inhibition of processes such as cell proliferation, migration, and invasion [53]. For example, adiponectin treatment has been shown to inhibit growth of HCC cells (HepG2, Huh7) in a dose-dependent manner; however, this effect was not observed when a normal human hepatocyte cell line (THLE-2) was treated with adiponectin [56].…”

Underlying Mechanisms behind the Brain–Gut–Liver Axis and Metabolic-Associated Fatty Liver Disease (MAFLD): An Update

“…IL-6 serves as a pivotal signal in ROS-induced liver injury, promoting cell proliferation and activating antiapoptotic pathways via the STAT3 signaling pathway, which is known for its oncogenic properties. Simultaneously, TNF-α contributes to disease progression and hepatocarcinogenesis by activating the JAK2/STAT pathway [43,60,82,83].…”

“…Thus, obesity is closely related to reduced adiponectin levels, as it reduces insulin sensitivity and increases liver fat levels. Furthermore, patients with NASH can show dysregulated postprandial glucose and lipid homeostasis, presenting a greater expression of AdipoR2 in liver tissue [43,61,74,82,141,142].…”

Potential Anti-Cancer Effects of Extra Virgin Olive Oil and Its Phenolic Extracts on Hepatocellular Carcinoma Cells

“…In the liver, EVOO has been shown to inhibit inflammation by reducing the production of tumor necrosis factor-α, a pro-inflammatory cytokine, thereby preventing liver damage that leads to HCC (Hatimy & Kadmiri, 2021). In addition, polyphenols suppress HCC cell proliferation and induce HCC cell apoptosis by inhibiting NF-κΒ activation (George et al, 2021;Vachliotis et al, 2023).…”