CircRNAs: versatile players and new targets in organ fibrosis.

Organ fibrosis can occur in virtually all major organs with relentlessly progressive and irreversible progress, ultimately resulting in organ dysfunction and potentially death. Unfortunately, current clinical treatments cannot halt or reverse the progression of fibrosis to end-stage organ failure, and thus, advanced antifibrotic therapeutics are urgently needed. In recent years, a growing body of research has revealed that circular RNAs (circRNAs) play pivotal roles in the development and progression of organ fibrosis through highly diverse mechanisms of action. Thus, manipulating circRNAs has emerged as a promising strategy to mitigate fibrosis across different organ types. In this review, we systemically summarize the current state of knowledge about circRNA biological properties and the regulatory mechanisms of circRNAs. A comprehensive overview of major fibrotic signaling pathways and representative circRNAs that are known to modulate fibrotic signals are outlined. Then, we focus on the research progress of the versatile functional roles and underlying molecular mechanisms of circRNAs in various fibrotic diseases in different organs, including the heart, liver, lung, kidney and skin. Finally, we offer a glimpse into the prospects of circRNA-based interference and therapy, as well as their utilization as biomarkers in the diagnosis and prognosis of fibrotic diseases. DCwYr1U-SPU-jT71MBGR_n Video abstract Key points: Aberrant expression of circRNA has been described in fibrotic states affecting different organs, including the lung, heart, liver, kidney and skin. Some circRNAs are closely associated with fibrogenesis through their effects on various fibrotic pathways. CircRNAs have anti- or pro-fibrotic effects depending on the downstream targeted molecules and pathways and might contribute to the regulation of inflammation, apoptosis, fibroblast activation and proliferation, and extracellular matrix accumulation. A substantial body of research has mainly focused on the well-known microRNA sponge role of circRNAs. Recently, new mechanisms, including interactions with proteins, coding capacities, and extracellular exosomal circRNAs, have been uncovered. Much research has examined fibrotic effector cells, particularly fibroblasts and myofibroblasts. The circ-transcriptome in other cell types, including epithelial, endothelial, and immune cells involved in fibrosis, needs to be profiled. Further work is needed to identify and validate circRNAs as biomarkers of the development and progression of fibrotic diseases. Although circRNAs are promising antifibrotic therapeutic targets, their clinical use remains far off. Purification of synthetic circRNAs and their safety are key issues that need to be solved before they can be successfully translated into clinical settings. [ABSTRACT FROM AUTHOR]