The Intriguing Roles of Cytokines in Metabolic Dysfunction-Associated Steatotic Liver Disease: A Narrative 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.

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.

Amounting evidence renders some cytokines key players in the pathophysiology of MASLD, which may possibly have diagnostic and therapeutic implications.