Inflammation at the Crossroads of MASLD: Immunological Mechanisms and Their Interconnections with Other Diseases

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as NAFLD, represents the most prevalent liver disorder globally, primarily resulting from unhealthy diets, obesity, and insulin resistance. MASLD includes conditions from simple steatosis (MASL) to metabolic-associated steatohepatitis (MASH), marked by liver injury, inflammation, and fibrosis. Inflammation is critical to progressing from MASL to MASH and contributes to comorbidities like type 2 diabetes, chronic renal disease, and cardiovascular disease. While past studies have highlighted the critical involvement of immune-mediated injury, the full extent of how immune responses orchestrate both local liver inflammation and systemic metabolic disturbances remains insufficiently understood.

Recent advances have identified the pivotal roles of both innate and adaptive immune systems, including Kupffer cells, monocyte-derived macrophages, neutrophils, innate lymphoid cells, NK/NKT cells, and T/B lymphocytes, in modulating MASLD pathogenesis. These immune cells contribute via cytokine, chemokine, and danger signal production, as well as through crosstalk with hepatocytes, stellate cells, and the hepatic microenvironment. Despite this progress, significant gaps remain regarding the molecular and cellular interplay underpinning MASLD heterogeneity, as well as the precise immune mechanisms that connect hepatic inflammation to extrahepatic metabolic dysfunction and disease burden. Critical challenges include identifying reliable immune biomarkers and unraveling therapeutic targets that can modify disease trajectory.

This Research Topic aims to advance our understanding of the immunopathogenesis of MASLD, elucidating how inflammatory and immune-mediated mechanisms drive disease initiation and progression and contribute to comorbid conditions. We particularly encourage submissions that explore immune cell activation, intracellular signaling, tissue cross-talk, and immunometabolic interactions at both the hepatic and systemic level. To foster innovation in treatment and diagnosis, we also seek studies highlighting novel immune-targeted therapies and clinically actionable biomarkers.

Research boundaries for this topic include the exploration of immunological mechanisms and therapeutic interventions specific to MASLD and related metabolic comorbidities. We welcome contributions on, but not limited to, the following key themes:
• Roles of innate and adaptive immune cells in MASLD onset and progression
• Cytokine and chemokine signaling, inflammasome activation, and pattern-recognition receptors in liver inflammation
• Interactions between hepatic cells and immune populations in fibrosis and tissue injury
• Local–systemic immune crosstalk and its impact on extrahepatic sites (e.g., cardiovascular and renal systems, diabetes)
• Influence of the gut–liver axis and microbiota-driven immunity on MASLD immunopathology
• Development and evaluation of immunomodulatory therapies targeting MASLD inflammation
• Discovery and validation of immune-related biomarkers for diagnostic and prognostic use
• Translational and clinical studies, including immune profiling and immunology-focused interventional trials in MASLD

We invite original research, reviews, mini-reviews, case reports, clinical trials, and perspectives that offer new insights into the immunological basis of MASLD. By bridging experimental and clinical immunology, this Research Topic aims to drive forward precision approaches for diagnosis and therapy, ultimately improving outcomes for individuals with MASLD and its metabolic complications.

Manuscripts that are not specifically focused on immunological aspects of MASLD are not in scope for Frontiers in Immunology.