Radiation-sensitive circRNA hsa_circ_0096498 inhibits radiation-induced liver fibrosis by suppressing EIF4A3 nuclear...

Area of Science:

• Hepatology
• Molecular Biology
• Oncology

Background:

• Radiation-induced liver fibrosis (RILF) is a significant complication of radiation therapy, primarily driven by activated hepatic stellate cells (HSCs).
• The role of circular RNAs (circRNAs) in the pathogenesis of RILF remains largely unexplored.

Purpose of the Study:

• To investigate the function and mechanism of circRNAs in radiation-induced liver injury (RILI) and subsequent fibrosis.
• To identify specific circRNAs involved in regulating hepatic stellate cell activation during RILF.

Main Methods:

• RNA pull-down, LC-MS/MS, and RNA immunoprecipitation to identify circRNA-protein interactions.
• RNA sequencing to determine circRNA-regulated gene expression.
• In vitro assays with HSCs and in vivo RILF mouse models to evaluate the therapeutic potential of circ96498 and CDC42 modulation.

Main Results:

• A novel radiation-sensitive circRNA, hsa_circ_0096498 (circ96498), was identified and found to be upregulated in irradiated HSCs.
• Circ96498 inhibits HSC proliferation, promotes apoptosis, reduces pro-inflammatory cytokines, and suppresses profibrotic markers.
• Mechanistically, circ96498 binds to EIF4A3, preventing nuclear translocation and subsequent CDC42 mRNA stabilization, thereby inhibiting HSC activation via NF-κB and JNK/Smad2 pathways.

Conclusions:

• The circ96498/EIF4A3/CDC42 axis plays a crucial role in suppressing radiation-induced HSC activation.
• Circ96498 acts as a protective factor against RILF.
• Modulation of this axis presents a promising therapeutic avenue for preventing and treating RILF.