CircRNAs in hepatic lipid metabolism: regulatory mechanisms and clinical implications

Hepatic lipid metabolism homeostasis is crucial for maintaining metabolic health, and its disruption is a central factor in the development of metabolic diseases such as non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD). Circular RNAs (circRNAs),a novel class of non-coding RNAs characterized by their covalently closed loop structures and remarkable stability, have emerged as key regulators of gene expression. Recent studies have revealed that circRNAs play significant roles in modulating critical hepatic lipid metabolism signaling pathways, including AMPK, mTOR, PPAR, and SREBP. This review systematically summarizes the latest advances in understanding how circRNAs influence these pathways through mechanisms such as acting as molecular sponges for microRNAs, interacting with proteins, and potentially encoding functional peptides. We critically evaluate the experimental models used in key studies, distinguishing between in vitro, in vivo, and clinical evidence, and discuss the context-dependent nature of circRNA function. Furthermore, the potential of circRNAs as diagnostic biomarkers and therapeutic targets for NAFLD and MASLD is discussed, highlighting their clinical relevance alongside a balanced assessment of the challenges facing clinical translation. By integrating current research findings, this review aims to provide a comprehensive theoretical foundation for elucidating the regulatory networks governing hepatic lipid metabolism and for developing innovative intervention strategies against metabolic liver diseases.