Critical role of interleukin-33 in pathogenesis and progression of metabolic dysfunction-associated steatotic liver disease

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as Non-alcoholic fatty liver disease (NAFLD) describes a diverse array of liver conditions linked to disrupted metabolic processes, ranging from hepatic steatosis and steatohepatitis to fibrosis, cirrhosis, and ultimately hepatocellular carcinoma (HCC). Currently, MASLD has progressively become a primary contributor to chronic liver disease globally. Due to its multifactorial etiology and varied clinical presentations, MASLD remains challenging in terms of accurate diagnosis and effective management. Accumulating evidence underscores the pivotal involvement of the interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) signaling pathway in critical aspects of MASLD pathophysiology, such as metabolic balance, oxidative stress response, intestinal barrier integrity, microbiota dynamics, inflammatory processes, hepatic fibrosis, and tumor development. IL-33 plays an exceptionally complex and central role in the pathophysiological processes of MASLD, and current evidence suggests that its actions may appear contradictory. Therefore, this review systematically integrates molecular insights into IL-33 biology and elucidates the regulatory networks underpinning IL-33/ST2 interactions, emphasizing their distinct roles at different MASLD stages. Furthermore, it is particularly noteworthy that IL-33 expression varies dynamically throughout disease progression. Additionally, the potential clinical utility of IL-33 as both a biomarker for early diagnosis and a therapeutic target is examined. By synthesizing fundamental and clinical research, this review aims to enhance the understanding of immunometabolic mechanisms involved in MASLD, thereby offering theoretical support and identifying future directions for personalized diagnostic and therapeutic approaches. The current research is largely limited to animal model studies, with a lack of longitudinal cohort studies in humans, which creates challenges for translational medicine.