Purpose of Review: To summarize experimental and clinical evidence on the association between tumor necrosis factor-α (TNF-α) and nonalcoholic fatty liver disease (NAFLD) and discuss potential treatment considerations. Recent Findings: Experimental evidence suggests that TNF-α is a cytokine with a critical role in the pathogenesis of NAFLD. Although, the production of TNF-α may be an early event during the course of nonalcoholic fatty liver (NAFL), TNF-α may play a more substantial role in the pathogenesis of nonalcoholic steatohepatitis (NASH) and NAFLD-associated fibrosis. Moreover, TNF-α may potentiate hepatic insulin resistance, thus interconnecting inflammatory with metabolic signals and possibly contributing to the development of NAFLD-related comorbidities, including cardiovascular disease, hepatocellular carcinoma, and extra-hepatic malignancies. In clinical terms, TNF-α is probably associated with the severity of NAFLD; circulating TNF-α gradually increases from controls to patients with NAFL, and then, to patients with NASH. Given this potential association, various therapeutic interventions (obeticholic acid, peroxisome proliferator-activated receptors, sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, probiotics, synbiotics, rifaximin, vitamin E, pentoxifylline, ursodeoxycholic acid, fibroblast growth factor-21, n-3 polyunsaturated fatty acids, statins, angiotensin receptor blockers) have been evaluated for their effect on TNF-α and NAFLD. Interestingly, anti-TNF biologics have shown favorable metabolic and hepatic effects, which may open a possible therapeutic window for the management of advanced NAFLD. Summary: The potential key pathogenic role of TNF-α in NAFLD warrants further investigation and may have important diagnostic and therapeutic implications.

Purpose of Review: To summarize evidence on the potential involvement of the osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B (NF-κΒ) ligand (RANKL)/receptor activator of NF-κΒ (RANK) axis in the pathogenesis of metabolic diseases. Recent Findings: The OPG-RANKL-RANK axis, which has been originally involved in bone remodeling and osteoporosis, is now recognized as a potential contributor in the pathogenesis of obesity and its associated comorbidities, i.e., type 2 diabetes mellitus and nonalcoholic fatty liver disease. Besides bone, OPG and RANKL are also produced in adipose tissue and may be involved in the inflammatory process associated with obesity. Metabolically healthy obesity has been associated with lower circulating OPG concentrations, possibly representing a counteracting mechanism, while elevated serum OPG levels may reflect an increased risk of metabolic dysfunction or cardiovascular disease. OPG and RANKL have been also proposed as potential regulators of glucose metabolism and are potentially involved in the pathogenesis of type 2 diabetes mellitus. In clinical terms, type 2 diabetes mellitus has been consistently associated with increased serum OPG concentrations. With regard to nonalcoholic fatty liver disease, experimental data suggest a potential contribution of OPG and RANKL in hepatic steatosis, inflammation, and fibrosis; however, most clinical studies showed reduction in serum concentrations of OPG and RANKL. Summary: The emerging contribution of the OPG-RANKL-RANK axis to the pathogenesis of obesity and its associated comorbidities warrants further investigation by mechanistic studies and may have potential diagnostic and therapeutic implications.

Purpose of Review: This narrative review aims to critically summarize evidence on the potential contribution of cytokines, including members of the tumor necrosis factor (TNF) superfamily, interleukins (ILs), interferons (IFs), chemokines, lymphokines, and members of the transforming growth factor (TGF) superfamily to the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). It also considers the translational relevance of cytokines, including their potential for non-invasive biomarkers or therapeutic targets of MASLD. Recent Findings: MASLD and its inflammatory phenotype, metabolic dysfunction-associated steatohepatitis (MASH), are characterized by chronic, low-grade hepatic inflammation, primarily initiated by metabolic contributors and driven by various cytokines. Cytokines are major mediators of the transition from hepatic steatosis to MASH. Some of them seem to be predominantly protective (tumor necrosis factor weak inducer of apoptosis, IL-10, IL-22, IL-25, IL-27), others appear to exhibit a possibly dual-faceted effect, depending on the stage of MASLD (TNF-α, TNF-related apoptosis-inducing ligand, IL-2, IL-6, IL-18, IL-33, IFNs), whereas a third group of cytokines seems to be predominantly harmful, thus driving the progression of hepatic steatosis to MASH, fibrosis, cirrhosis, and possibly to hepatocellular carcinoma. In this regard, some cytokines may prove suitable non-invasive indices for distinguishing MASH or hepatic fibrosis from hepatic steatosis. Additionally, cytokine-based therapies, including anti-TNF-α agents (infliximab, adalimumab, etanercept), NLRP3 inhibitors, recombinant IL-1R antagonist (anakinra), selective C-C chemokine receptor type 2 inhibitors, anti-IL-17 (e.g., secukinumab and ixekizumab) or IL-17R (brodalumab) monoclonal antibodies, and recombinant IL-22, may prove promising pharmacological targets for the management of MASLD. Summary: Amounting evidence renders some cytokines key players in the pathophysiology of MASLD, which may possibly have diagnostic and therapeutic implications.

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.