Noncoding RNAs and RNA-binding proteins: emerging governors of liver physiology and metabolic diseases

The liver holds central roles in detoxification, energy metabolism, and whole body homeostasis but can develop malignant phenotypes when being chronically overwhelmed with fatty acids and glucose. The global rise of metabolic dysfunction -associated fatty liver disease (MAFLD) is already affecting a quarter of the global population. Pharmaceutical treatment options against different stages of MAFLD do not yet exist, and several clinical trials against hepatic transcription factors and other proteins have failed. However, emerging roles of noncoding RNAs, including long (lncRNA) and short noncoding RNAs (sRNA), in various cellular processes pose exciting new avenues for treatment interventions. Actions of noncoding RNAs mostly rely on interactions with proteins, whereby the noncoding RNA fine-tunes protein function in a process termed riboregulation. The developmental stage-, disease stage-, and cell type-specific nature of noncoding RNAs harbors enor-mous potential to precisely target certain cellular pathways in a spatiotemporally defined manner. Proteins interacting with RNAs can be categorized into canonical or noncanonical RNA-binding proteins (RBPs) depending on the existence of classi-cal RNA-binding domains. Both, RNA-and RBP-centric methods have generated new knowledge of the RNA-RBP interface and added an additional regulatory layer. In this review, we summarize recent advances in how RBP-lncRNA interactions and various sRNAs shape cellular physiology and the development of liver diseases such as MAFLD and hepatocellular carcinoma.

Automated summary

The liver plays important roles in detoxification, energy metabolism, and whole body homeostasis. However, chronic overload of fatty acids and glucose can lead to the development of malignant phenotypes in the liver. The global increase in metabolic dysfunction-associated fatty liver disease (MAFLD) is affecting a significant portion of the population. Noncoding RNAs, including long and short noncoding RNAs, have emerged as potential targets for treatment interventions. The interactions between noncoding RNAs and proteins offer precise ways to target specific cellular pathways.