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

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the leading cause of chronic liver disease worldwide, affecting approximately 25-30% of the global adult population and highlighting the urgent need for effective therapeutics and prevention strategies. MASLD is characterized by excessive hepatic lipid accumulation and can progress, in a subset of patients, to metabolic dysfunction-associated steatohepatitis (MASH), a pro-inflammatory and pro-fibrotic condition associated with increased risk of liver cirrhosis and hepatocellular carcinoma. Although the molecular drivers of MASLD progression remain incompletely understood, several key metabolic pathways-such as triglyceride handling, cholesterol catabolism, bile acid metabolism, mitochondrial function, and autophagy-are consistently dysregulated in MASLD livers. This narrative review summarizes primary literature and highlights insights from recent reviews on the multifaceted role of the mRNA-binding protein Human antigen R (HuR) in the post-transcriptional regulation of critical cellular processes, including nutrient metabolism, cell survival, and stress responses. Emerging evidence underscores HuR's essential role in maintaining liver homeostasis, particularly under metabolic stress conditions characteristic of MASLD, with hepatocyte-specific HuR depletion associated with exacerbated disease severity. Moreover, comorbid conditions such as obesity, type 2 diabetes mellitus, and cardiovascular disease not only exacerbate MASLD progression but also involve HuR dysregulation in extrahepatic tissues, further contributing to liver dysfunction. A deeper understanding of HuR-regulated post-transcriptional networks across metabolic organs may enable the development of targeted therapies aimed at halting or reversing MASLD progression.

Keywords: RNA binding proteins; hepatic steatosis; human antigen R (HuR); metabolic dysfunction-associated steatotic liver disease (MASLD); metabolic syndrome; non-alcoholic fatty liver disease (NAFLD); post-transcriptional regulation.

Figure 1.

Schematic overview of HuR structure, function, and regulatory mechanisms. HuR (Human antigen R) contains three highly conserved RNA recognition motifs (RRMs) connected by flexible hinge and linker domains. The HuR nucleocytoplasmic shuttling sequence (HNS) enables HuR to move between the nucleus and cytoplasm. HuR binds directly to target mRNAs by recognizing adenine- and uridine-rich elements (AREs) through its RRMs, classically exemplified by its interaction with transcripts such as the Fos proto-oncogene (c-fos). The regulation of HuR expression and activity is multifactorial. Transcriptional regulators of HuR include nuclear factor kappa B (Nf-κB) and mothers against decapentaplegic homolog (SMAD). At the post-transcriptional level, HuR positively autoregulates its own expression, while ARE/poly(U)-binding degradation factor 1 (AUF1) and several miRNAs, including miR-22/29/519, negatively regulate HuR. Several post-translational modifications, including phosphorylation (P) by protein kinase C (PKC) and cyclin-dependent kinase 1 (Cdk1), methylation (Me) by coactivator-associated arginine methyltransferase 1 (CARM1), and protein cleavage mediated by cysteine- and aspartate-protease family members Casp3/7 (caspase 3/7). Protein–protein interactions collectively govern its localization and functional output. Under homeostatic conditions, HuR is predominantly localized in the nucleus, where it binds to introns and splice sites of pre-mRNAs to regulate pre-mRNA processing. In response to cellular stress, HuR protein translocates to the cytoplasm, where it enhances stability and translation of mature mRNA targets involved in stress response, survival, inflammation, and metabolism. Created in BioRender V2 https://BioRender.com/z74o1fi. (accessed on 1 July 2025).

Figure 2.

Graphical summary of HuR’s roles in liver homeostasis and MASLD pathogenesis. HuR plays a multifaceted role in maintaining hepatic homeostasis and regulating key processes implicated in MASLD development. These include electron transport chain activity and mitochondrial function, hepatic stellate cell (HSC) activation and fibrogenesis, insulin signaling via the phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase 1 (AKT1) pathway, lipoprotein assembly and VLDL secretion, and bile acid synthesis and metabolism. HuR directly or indirectly regulates the expression of a wide array of target transcripts involved in these pathways, including NADH ubiquinone oxidoreductase subunit B6 (Ndufb6), ubiquinol–cytochrome c reductase binding protein (Uqcrb), cytochrome C (Cytc), osteopontin (Opn), H19, phosphatase and tensin homolog (Pten), apolipoprotein b (Apob), apolipoprotein e (Apoe), cytochrome P450 family 7 subfamily A member 1 (Cyp7a1), and cytochrome P450 family 7 subfamily B member 1 (Cyp7b1). Collectively, these regulatory activities position HuR as a key post-transcriptional mediator in both physiological liver function and MASLD progression. Created in BioRender V2. https://BioRender.com/qshr340. (accessed on 1 July 2025).