Ferritinophagy is a crucial cellular pathway that selectively degrades ferritin to release free iron and plays a key role in maintaining intracellular iron homeostasis. Recent studies have shown a close relationship between viral infections and host iron metabolism. As a significant pathogen severely affecting the global swine industry， the relationship between PRRSV replication and host ferritinophagy remains unclear.CRISPR/Cas9 technology was used to knockout the NCOA4 gene encoding a key receptor for ferritinophagy in PRRSV-susceptible MARC-145 cells to study the role of NCOA4-mediated ferritinophagy in the infection of PRRSV. The efficiency of knockouting the NCOA4 gene was detected with Sanger sequencing and Western blot. Methods including flow cytometry， QPCR， Western blot and TCID₅₀ assays were used to detect the cell cycle and cell viability of the NCOA4 deficient mutant and wild-type MARC-145， and study the effect of NCOA4 deficiency on the replication of PRRSV. The results showed that MARC-145 cell lines with NCOA4 gene knockout were successfully constructed. The level of ORF7 mRNA， N protein， and viral titers of PRRSV in MARC-145 cell lines with NCOA4 gene knockout was significantly increased and the expression of FTH1 protein was promoted compared with that in wild-type MARC-145 cells. It is indicated that the deletion of NCOA4， a key receptor gene for ferritinophagy， can promote the replication of PRRSV. It will provide a theoretical basis for the prevention and control of PRRSV.