Objective:To evaluate the effect of long non-coding RNA PRMT5-AS1 on ferroptosis of hepatocellular carcinoma cell(HCC) after ionizing irradiation.Methods:The PRMT5-AS1 overexpression model was constructed in MHCC-97H cells and the PRMT5-AS1 knockdown model was constructed in HepG2 cells. X-ray irradiation(IR) was performed with an absorbed dose of 10 Gy and a dose rate of 3 Gy/min. Western blot and qRT-PCR were used to detect gene expression. The effect of PRMT5-AS1 expression on lipid peroxidation and ferroptosis of HCC after IR was detected by Trypan blue staining flow cytometry. The effect of PRMT5-AS1 expression on the death of HCC after IR was detected by CCK-8 assay. Dual luciferase assay to detect the binding of let-7c-5p to PRMT5-AS1 and SLC7A11.Results:Overexpression of PRMT5-AS1 in MHCC-97H cells could significantly reduce cell death induced by IR (Vector vs. PRMT5-AS1: 27.57% vs.18.30%, t=14.94, P<0.05). Knockdown of PRMT5-AS1 in HepG2 cells significantly increased cell death induced by IR (siNC vs. siPRMT5-AS1: 17.26% vs. 28.26%, t=13.63, P<0.05). Flow cytometry result show that overexpression of PRMT5-AS1 can significantly inhibit the increase of intracellular lipid ROS level induced by IR (Vector vs. PRMT5-AS1: 17.01% vs. 12.52%, t=12.80, P<0.05), and knockdown of PRMT5-AS1 significantly increases the lipid ROS level induced by IR (siNC vs. siPRMT5-AS1: 14.54% vs. 17.72%, t=5.93, P<0.05). The result of CCK-8 experiment showed that overexpression of PRMT5-AS1 could significantly inhibit Erastin induced cell activity reduction (Vector vs. PRMT5-AS1: 87.92% vs. 109.06%, t=2.87, P<0.05), and knockdown of PRMT5-AS1 could promote Erastin′s inhibitory effect on cell activity (siNC vs. siPRMT5-AS1: 82.56% vs. 60.58%, t=38.35, P<0.05). Western blot and fluorescent quantitative PCR result showed that the protein and mRNA levels of SLC7A11 were significantly increased after overexpression of PRMT5-AS1 ( t=26.24, P<0.05), and the protein and mRNA levels of SLC7A11 were significantly decreased after knockdown of PRMT5-AS1 ( t=5.60, P<0.05). The correlation between PRMT5-AS1 and let-7c-5p was confirmed by luciferase report gene experiment ( t=9.74, P<0.05). The result of luciferase reporter gene experiment showed that PRMT5-AS1 could form ceRNA network with let-7c-5p to regulate SLC7A11. Let-7c-5p was able to reverse the increase in SLC7A11 expression levels, decrease in Lipid-ROS levels and cell death induced by overexpression of PRMT5-AS1 ( t=3.01, 4.11, P<0.05). And knockdown of SLC7A11 reversed Lipid-ROS inhibition and reduced cell death caused by PRMT5-AS1( t=21.35, 7.15, P<0.05). Conclusions:LncRNA PRMT5-AS1 inhibits IR-induced ferroptosis in HCC through the PRMT5-AS1/let-7c-5p/SLC7A11 axis.