Title: PRMT5 imposed a dual repression on DDIT3 transcription to promote the malignancy of hepatocellular carcinoma. This study reveals a novel molecular mechanism that drives the malignant progression of hepatocellular carcinoma. Specifically, the study found that PRMT5 can not only directly bind to the promoter region of DDIT3 but also catalyze the symmetric dimethylation of arginine at the 3rd position of histone H4, thereby directly inhibiting its transcriptional activity. The authors found that PRMT5 also acts as an adaptor protein, interacting with the transcription factor STAT3 and recruiting it to the DDIT3 promoter region, forming a complex that synergistically inhibits DDIT3 expression, ultimately leading to malignant liver cancer growth. Importantly, this study confirmed, through in vitro and in vivo experiments, that the PRMT5-specific inhibitor HLCL-61 can significantly inhibit liver cancer cell proliferation and tumor growth.