Integrated Transcriptomics Reveals a SHEV ORF3-Mediated circRNA Network That Disrupts Riboflavin Metabolism and...

Area of Science:

• Virology
• Molecular Biology
• Metabolic Homeostasis

Background:

• The Swine hepatitis E virus (SHEV) ORF3 protein's role in host metabolic regulation via RNA networks is not fully understood.
• Understanding these mechanisms is crucial for elucidating viral pathogenesis and host-pathogen interactions.

Purpose of the Study:

• To investigate how the SHEV ORF3 protein-mediated circRNA-miRNA network influences riboflavin metabolism and pancreatic cancer pathways.
• To evaluate potential physical interactions between viral proteins and host factors using advanced structural simulations.

Main Methods:

• High-throughput RNA sequencing to identify regulatory networks.
• KEGG pathway analysis to pinpoint affected biological pathways.
• AlphaFold 3 structural simulations to assess protein-RNA interactions.

Main Results:

• Transcriptomic analysis revealed dual activation of Riboflavin metabolism and Pancreatic cancer pathways.
• An "ENPP Isozyme Switch" was identified, involving hsa_circ_0077855 sponging miR-181a-2-3p, upregulating ENPP3 and KRAS.
• AlphaFold 3 simulations refuted direct physical binding, while SHEV ORF3 was found to suppress the m6A eraser FTO, indicating epigenetic instability.

Conclusions:

• SHEV ORF3 induces metabolic remodeling via a dual epigenetic-post-transcriptional mechanism.
• This involves disrupting m6A homeostasis by suppressing FTO and creating a pathogenic ceRNA network through the ENPP3/miR-181a/KRAS axis.
• Non-coding RNAs play a critical role in virus-induced pre-pathological states.