Study on the Mechanism of QRICH1 Mediating PRMT1 to Regulate the Arginine Methylation Modification of cGAS to Promote Arsenics-Induced Pyroptosis in Hepatocellular Carcinoma Cells

Jiayuan Zhang,1,2,* Tian Tian,3,* Shanshan Tian,1,2 Jinhai Yao,1,2 Yingwan Zhang,4 Rujia Xie,1,2 Ting Yang,1,2 Bing Han1,2 1Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China; 2Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China; 3Department of Eugenic Genetics, Guiyang Maternal and Child Health Care Hospital, Guiyang, Guizhou, 550003, People’s Republic of China; 4Qianxinan People’s Hospital, Qianxinan Affiliated Hospital of Zunyi Medical University, Xingyi, Guizhou, 562400, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bing Han, Email [email protected]: This study aims to investigate the mechanism of action of arsenic-based agents against hepatocellular carcinoma (HCC) and to identify effective drug targets for HCC treatment.Methods: Huh7 and HepG2 cells treated with NaAsO2 were assessed for cell viability, pyroptosis, migration, and invasion after undergoing lentiviral transfection. An orthotopic liver tumor model was established and divided into a model group and a treatment group. Proteins associated with QRICH1, PRMT1, cGAS-STING, and the classical pyroptosis pathway were quantified using Western blotting. The intracellular expression and localization of PRMT1 and NLRP3 in HCC were analyzed through cellular immunofluorescence. Co-immunoprecipitation (Co-IP) was performed to examine the protein interactions between PRMT1 and cGAS, as well as between STING and NLRP3. Chromatin immunoprecipitation (ChIP) was used to confirm QRICH1 enrichment in the PRMT1 promoter region.Results: NaAsO2 treatment significantly inhibited the proliferation of Huh7 and HepG2 cells and effectively blocked their migration and invasion capabilities, while promoting cellular pyroptosis. Quantitative polymerase chain reaction(QRCR) and ChIP assays confirmed that NaAsO2 regulates PRMT1 expression by down-regulate QRICH1 binding in the PRMT1 promoter region. Additionally, NaAsO2 decreased the expression of the QRICH1-PRMT1 complex and upregulated the cGAS-STING signaling pathway, activating the downstream NLRP3-dependent classical pyroptosis pathway. Overexpression of QRICH1 reversed these effects.Conclusion: NaAsO2 inhibits the expression of the QRICH1-PRMT1 axis, activates cGAS-STING signaling pathway transduction, and induces pyroptosis in HCC cells, thereby increasing the infiltration of immune cells in liver cancer tissues.Keywords: HCC, QRICH1, PRMT1, cGAS-STING, pyroptosis, NaAsO2