Background:Knockdown of ribosomal RNA processing 15 homolog(RRP15)inhibited the proliferation and growth of hepatocellular carcinoma(HCC),but its relationship with the sensitivity of HCC to sorafenib has not been reported.Aims:To elucidate the role of RRP15 in modulating the sensitivity of HCC to sorafenib and to unravel the underlying mechanisms.Methods:The constitutive expression of RRP15 in human HCC cell lines was assessed using real-time PCR and Western blotting,and then manipulated via infection with either RRP15 knockdown or overexpression lentivirus.The impact of RRP15 expression on sorafenib sensitivity of HCC cells was investigated by CCK-8 and colony formation assays.Changes in ferroptosis markers,including reactive oxygen species(ROS),Fe2+,lipid peroxide,reduced glutathione,etc in HCC cells were measured to determine the effect of RRP15 on ferroptosis.The combination of the ferroptosis inhibitor Ferrostatin-1 and RRP15 knockdown was used to verify the modulatory effect of RRP15 on sorafenib sensitivity and ferroptosis.Furthermore,xenograft tumor in nude mice was used to confirm the relationship between RRP15 and sorafenib sensitivity.Results:Sorafenib treatment induced RRP15 expression in HCC cells.The expression levels of RRP15 in HCC cells were negatively associated with the sensitivity to sorafenib.RRP15 knockdown enhanced the sorafenib sensitivity and sorafenib-induced ferroptosis in HCC cells,presenting as reduced cell viability,decreased colony formation ability,and increased intracellular ROS,Fe2+,and lipid peroxidation.Treatment with Ferrostatin-1 effectively compromised the increased ferroptosis and sorafenib sensitivity caused by RRP15 downregulation.Mechanistically,inactivation of p62-KEAP1-NRF2 pathway was involved in the RRP15 depletion-mediated ferroptosis and sorafenib sensitization in HCC cells.In in vivo study,RRP15 knockdown combined with sorafenib treatment notably inhibited the subcutaneous xenograft tumor growth in nude mice.Conclusions:This study demonstrates that inhibition of RRP15 significantly enhances the sensitivity of HCC to sorafenib,potentially through the promotion of ferroptosis.These findings may provide new strategies for improving the therapeutic response of HCC to sorafenib treatment.