Decoding RNA's Circular Decisions: How HNRNPD Shapes circRNA Biogenesis And RNA Fate
By Chen Liang, Ph.D., Researcher, University of Science and Technology of China
As the RNA therapeutics field continues to expand beyond traditional mRNA platforms, circular RNAs (circRNAs) are emerging as an increasingly important area of research. Their unique structural properties, including enhanced stability compared with many linear RNA molecules, have generated interest in their potential applications across protein replacement, immunotherapy, regenerative medicine, and other therapeutic areas.
However, translating circRNAs into robust therapeutic platforms requires a deeper understanding of the biological mechanisms that control their formation. While advances in RNA engineering have enabled researchers to design increasingly sophisticated molecules, many fundamental questions remain about how cells determine whether a transcript becomes a circular RNA or a conventional linear RNA.
In a recent study, my team investigated the role of the RNA-binding protein HNRNPD in regulating circRNA biogenesis and discovered that this factor influences the balance between circRNA and messenger RNA production for a subset of genes.
These findings provide new insight into the molecular processes that shape RNA fate and highlight the importance of understanding endogenous RNA regulation as researchers work to develop more predictable and effective RNA-based medicines.
Revealing The Regulatory Landscape Of circRNA Production
CircRNA formation is controlled by a complex interplay of transcriptional and post-transcriptional mechanisms. During RNA processing, transcripts can follow different pathways, producing either linear RNAs that are translated into proteins or circular RNAs with distinct biological functions.
Although thousands of circRNAs have been identified across different cell types and organisms, the mechanisms determining when and where these molecules are produced remain incompletely understood. This knowledge gap represents an important challenge for therapeutic development. A better understanding of circRNA regulation could provide researchers with new strategies for improving circRNA design, optimizing production, and controlling expression profiles for therapeutic applications.
Our work focused on HNRNPD, an RNA-binding protein involved in multiple aspects of RNA metabolism. We found that HNRNPD regulates circRNA formation for specific genes and affects the relative production of circular and linear RNA isoforms. Importantly, our findings suggest that circRNA generation is not simply a passive consequence of RNA splicing. Instead, it is an actively regulated process influenced by specific cellular factors that guide RNA-processing decisions.
HNRNPD And The Control Of RNA Fate
One of the broader implications of this research is that RNA biology is governed by highly coordinated regulatory networks. The sequence of an RNA molecule provides essential information, but the cellular environment and molecular machinery surrounding that RNA ultimately influence its fate.
By modulating the balance between circRNA and mRNA production, regulatory proteins such as HNRNPD help determine how genetic information is processed and utilized within cells. This concept has important implications for the future development of circRNA-based therapeutics. Engineering a successful circRNA medicine requires more than generating a circular molecule — it requires an understanding of how that molecule will behave inside the cell.
Factors such as circularization efficiency, stability, intracellular localization, and duration of expression all influence therapeutic performance. By studying the natural mechanisms that regulate circRNA production, researchers can begin to identify principles that may improve synthetic circRNA design.
Rather than approaching circRNA development solely from an engineering perspective, incorporating knowledge from endogenous RNA regulation may enable more precise and predictable therapeutic platforms.
Building The Foundation For Next-Generation RNA Medicines
The therapeutic potential of circRNAs continues to attract significant interest because of their ability to provide sustained RNA expression. This characteristic may offer advantages for applications where prolonged protein production is desirable.
However, several challenges remain before circRNA therapeutics can reach their full potential. These include improving manufacturing approaches, controlling expression levels, ensuring appropriate cellular activity, and understanding how engineered circRNAs interact with endogenous RNA pathways.
Research into circRNA regulatory mechanisms can help address these challenges by revealing the biological factors that influence RNA behavior. Our findings on HNRNPD provide another piece of this regulatory framework. By identifying a factor that shapes the balance between circRNA and mRNA production, this work contributes to a broader understanding of how cells control RNA output.
These insights may ultimately support the development of improved circRNA platforms, while also advancing our understanding of how disruptions in RNA processing contribute to disease.
Moving Toward Precision Control Of RNA Biology
The next phase of RNA therapeutics will depend not only on creating new RNA molecules but also on controlling how those molecules are processed, regulated, and maintained within cells. As researchers explore increasingly diverse RNA modalities, understanding the biological rules governing RNA fate will become essential. The ability to predict and manipulate RNA processing decisions could determine how effectively emerging platforms move from discovery into therapeutic applications.
Our study highlights the importance of investigating the molecular networks that regulate circRNA production. By understanding these pathways, we can better define the opportunities and challenges associated with developing circRNA-based medicines.
The future of RNA therapeutics will be shaped by both innovation in molecular engineering and a deeper understanding of the biology that governs RNA behavior. Continued exploration of regulators such as HNRNPD will help provide the foundation needed to design RNA medicines with greater stability, precision, and therapeutic potential.
About The Author
Chen Liang, Ph.D., is a specially appointed, dual-appointed researcher in the Department of Biomedical Sciences at the University of Science and Technology of China (USTC) and a researcher at the First Affiliated Hospital of USTC. He received his doctorate in biochemistry and molecular biology from USTC and has focused his research on understanding how non-coding RNAs regulate cellular homeostasis and contribute to the development of major diseases.