Tumor necrosis factor-α signaling in nonalcoholic steatohepatitis and targeted therapies

Nonalcoholic steatohepatitis (NASH), an inflammatory subtype of nonalcoholic fatty liver disease, is featured by significantly elevated levels of various proinflammatory cytokines. Among numerous proinflammatory factors that contribute to NASH pathogenesis, the secreted protein, tumor necrosis factor-alpha (TNF-α), plays an essential role in multiple facets of NASH progression and is therefore considered as a potential therapeutic target. In this review, we will first systematically describe the preclinical studies on the biochemical function of TNF-α and its intracellular downstream signaling mechanisms through its receptors. Moreover, we extensively discuss its functions in regulating inflammation, cell death, and fibrosis of liver cells in the pathogenesis of NASH, and the molecular mechanism that TNF-α expression is regulated by NF-κB and other upstream master regulators during NASH progression. As TNF-α is one of the causal factors that remarkably contributes to NASH progression, combination of therapeutic modalities, including TNF-α-based therapies may lead to the resolution of NASH via multiple pathways and thus generate clinical benefits. For translational studies, we summarize recent advances in strategies targeting TNF-α and its signaling pathway, which paves the way for potential therapeutic treatments for NASH in the future.