Radiation-sensitive circRNA hsa_circ_0096498 inhibits radiation-induced liver fibrosis by suppressing EIF4A3 nuclear translocation to decrease CDC42 expression in hepatic stellate cells

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BACKGROUND: Radiation-induced liver fibrosis (RILF) is a common manifestation of radiation-induced liver injury (RILI) and is caused primarily by activated hepatic stellate cells (HSCs). Circular RNAs (circRNAs) play critical roles in various diseases, but little is known about the function and mechanism of circRNAs in RILF. METHODS: RNA pull-down and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to screen binding proteins of hsa_circ_0096498 (circ96498). RNA-binding protein immunoprecipitation, RNA pull-down and nuclear and cytoplasmic protein extraction were conducted to confirm the interaction between circ96498 and eukaryotic initiation factor 4A3 (EIF4A3). RNA sequencing was performed to screen target genes regulated by EIF4A3. HSCs with altered circ96498 and cell division cycle 42 (CDC42) expression were used to assess irradiated HSC activation. Circ96498 inhibition and CDC42 blockade were evaluated in RILF mouse models. RESULTS: In this study, we identified a radiation-sensitive circ96498, which was highly expressed in the irradiated HSCs of paracancerous tissues from RILI patients. Circ96498 inhibited the proliferation but promoted the apoptosis of irradiated HSCs, suppressed the secretion of proinflammatory cytokines IL-1β, IL-6 and TNF-α, and decreased the expression of profibrotic markers (α-SMA and collagen 1) in irradiated HSCs. Mechanistically, irradiation induced the transport of EIF4A3 into the nucleus, and nuclear EIF4A3 increased the stability of CDC42 mRNA and increased CDC42 expression, thereby promoting HSC activation through the NF-κB and JNK/Smad2 pathways. However, the binding of circ96498 to EIF4A3 impeded the translocation of EIF4A3 into the nucleus, resulting in the inhibition of CDC42 expression and subsequent HSC activation. Furthermore, circ96498 knockdown promoted the development of the early and late stages of RILF in a mouse model, which was mitigated by CDC42 blockade. CONCLUSIONS: Collectively, our findings elucidate the involvement of the circ96498/EIF4A3/CDC42 axis in inhibiting irradiated HSC activation, which offers a novel approach for RILF prevention and treatment.

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