From steatosis to inflammation: Innate lymphocytes as hidden orchestrators in metabolic dysfunction-associated steatotic liver disease

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive condition that ranges from simple hepatic steatosis to steatohepatitis, persistent inflammation, and fibrosis. Although metabolic alterations and hepatocellular injury are established as central drivers of MASLD, accumulating evidence underscores the pivotal contribution of innate and innate-like lymphocytes in modulating immune responses throughout disease progression. Among these, gamma delta T cells, natural killer cells, natural killer T cells, innate lymphoid cells, and mucosal-associated invariant T cells are highly represented in the liver and rapidly respond to metabolic stress and inflammatory stimuli. These populations promote cytokine secretion, hepatocyte injury, recruitment of additional immune subsets, and activation of hepatic stellate cells, thereby sustaining inflammation and tissue remodeling. Depending on the disease stage and the surrounding microenvironment, they may exert either protective or pathogenic roles, ultimately determining whether the process resolves or progresses toward fibrosis. This review provides an overview of their phenotypic features, effector mechanisms, and interactions within the hepatic immune microenvironment, highlighting their potential as diagnostic biomarkers and therapeutic targets in MASLD and its complications.

Keywords: Innate lymphocytes cells; Gamma delta T cells; Mucosal-associated invariant T cells; Natural killer cells; Natural killer T cell; Metabolic dysfunction-associated steatotic liver disease; Fibrosis

Core Tip: Metabolic dysfunction-associated steatotic liver disease is now recognized as a leading cause of chronic liver disease worldwide. Beyond metabolic stress and hepatocellular injury, recent evidence highlights the critical involvement of innate and innate-like lymphocytes, such as gamma delta T cells, natural killer cells, natural killer T cells, innate lymphoid cells, and mucosal-associated invariant T cells in driving inflammation, hepatocyte injury, and hepatic stellate cell activation. Depending on the microenvironment, these cells may exert protective or pathogenic roles, shaping progression toward steatohepatitis and fibrosis. Understanding their effector functions offers opportunities for novel biomarkers and therapeutic strategies in metabolic dysfunction-associated steatotic liver disease.