乙型肝炎病毒X蛋白（HBx）是肝细胞癌（HCC）乙型肝炎病毒（HBV）诱导的已知原因。尚未有关精氨酸甲基化是否调节HBx诱导的HCC进展中的铁死亡的报道。本研究旨在探索HBx调节的蛋白精氨酸甲基转移酶9（PRMT9）是否介导了铁死亡参与HCC发展。 HBx通过促进HCC细胞中PRMT9的表达来抑制铁死亡。PRMT9在体内抑制铁死亡以加速HCC进展。PRMT9靶向HSPA8，并增强在HCC中HSPA8的精氨酸甲基化在R76和R100上以调节铁死亡。HSPA8的过表达改变了HepG2细胞的转录组谱，尤其是铁死亡和免疫相关通路通过不同表达基因明显富集，包括CD44。HSPA8的过表达上调了CD44的表达，而CD44的沉默显著逆转了PRMT9过表达引起的铁死亡的抑制。 综上所述，HBx/PRMT9/HSPA8/CD44轴是调节HCC细胞中铁死亡的重要信号通路。本研究为治疗HBV诱导的HCC提供了新的机会和靶点。 © 2023. BioMed Central Ltd., part of Springer Nature.

The hepatitis B virus X (HBx) protein is an established cause of hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC). Whether arginine methylation regulates ferroptosis involved in HBx-induced HCC progression has not been reported. This study aimed to explore whether HBx-regulated protein arginine methyltransferase 9 (PRMT9) mediates the involvement of ferroptosis in the development of HCC.HBx inhibited ferroptosis through promoting PRMT9 expression in HCC cells. PRMT9 suppressed ferroptosis to accelerate HCC progression in vivo. PRMT9 targeted HSPA8 and enhanced arginine methylation of HSPA8 at R76 and R100 to regulate ferroptosis in HCC. HSPA8 overexpression altered the transcriptome profile of HepG2 cells, in particular, ferroptosis and immune-related pathways were significantly enriched by differentially expressed genes, including CD44. HSPA8 overexpression up-regulated CD44 expression and knockdown of CD44 significantly reversed the inhibition of ferroptosis caused by PRMT9 overexpression.In conclusion, HBx/PRMT9/HSPA8/CD44 axis is a vital signal pathway regulating ferroptosis in HCC cells. This study provides new opportunities and targets for the treatment of HBV-induced HCC.© 2023. BioMed Central Ltd., part of Springer Nature.