CircRNAs critically regulate hepatic lipid metabolism via AMPK, mTOR, PPAR, and SREBP pathways

Maintaining hepatic lipid metabolism homeostasis is vital for overall metabolic health, as its disruption is a primary driver of non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD). These conditions, characterized by excessive lipid accumulation in the liver, can lead to systemic metabolic dysregulation and severe liver damage. Current therapeutic strategies often fall short, highlighting an urgent need for novel targets. Circular RNAs (circRNAs), a stable class of non-coding RNAs, have emerged as significant modulators of gene expression, offering a promising avenue for understanding and intervening in these complex metabolic disorders.

This systematic review synthesized the latest research on circRNAs' roles in hepatic lipid metabolism, evaluating findings from diverse experimental models including in vitro cell culture studies, in vivo animal models, and emerging clinical evidence. The authors critically assessed the regulatory mechanisms by which circRNAs influence key signaling pathways. They also discussed the potential of circRNAs as diagnostic biomarkers and therapeutic targets for NAFLD and MASLD, providing a balanced perspective on the challenges associated with their clinical translation and the context-dependent nature of their functions.

CircRNAs are established as crucial regulators of hepatic lipid metabolism, influencing several critical signaling pathways. They primarily exert their effects through mechanisms such as acting as molecular sponges for microRNAs, directly interacting with proteins, and potentially encoding functional peptides. The review highlighted circRNA modulation of key metabolic pathways including AMPK, mTOR, PPAR, and SREBP, which are central to lipid synthesis, breakdown, and transport in the liver. These regulatory actions underscore circRNAs' profound impact on maintaining or disrupting lipid homeostasis. The authors emphasized that circRNAs' covalently closed loop structures contribute to their remarkable stability, making them attractive candidates for therapeutic intervention.

The systematic analysis revealed that circRNAs modulate critical hepatic lipid metabolism pathways, suggesting their broad involvement in the pathogenesis of NAFLD and MASLD.