Multifaceted Human Antigen R: A Key Player in Liver Metabolism and MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the leading cause of chronic liver disease worldwide, posing a substantial public health burden and underscoring the urgent need for effective therapeutic and preventive strategies. MASLD is defined by excessive hepatic lipid accumulation and, in a subset of patients, progresses to metabolic dysfunction-associated steatohepatitis (MASH), a pro-inflammatory and pro-fibrotic condition associated with increased risk of fibrosis, cirrhosis, and hepatocellular carcinoma. Although the mechanisms driving MASLD progression remain incompletely understood, dysregulation of key metabolic pathways, including triglyceride handling, cholesterol catabolism, bile acid metabolism, mitochondrial function, and autophagy, has been consistently observed in MASLD livers. Human antigen R (HuR), a ubiquitously expressed mRNA-binding protein, is a post-transcriptional regulator of diverse cellular processes, including nutrient metabolism, cell survival, and stress responses. Recent evidence highlights HuR’s critical role in maintaining hepatic homeostasis, particularly under conditions of metabolic stress, such as those found in MASLD. Moreover, comorbid metabolic diseases, including obesity, type 2 diabetes mellitus, and cardiovascular disease, not only exacerbate MASLD severity but also involve HuR dysregulation in extrahepatic tissues, further contributing to hepatic dysfunction. This review explores the dynamic and cell-type–specific roles of HuR in MASLD pathogenesis and its associated metabolic comorbidities. A deeper understanding of HuR’s post-transcriptional regulatory networks across metabolic tissues may inform the development of targeted therapies aimed at preventing or reversing MASLD progression.