As an ultra-early response gene, Nuclear receptor 4A1 (NR4A1) has been reported to be involved in the development of various diseases through various pathological pathways, but its specific mechanism in chronic kidney disease (CKD) is unknown currently. Our study showed that the expression of NR4A1 was reduced in unilateral ureteral obstruction (UUO) mice and it could exacerbate UUO-induced renal pathological injury when knocked down NR4A1 in UUO mice. We found that the knockdown of NR4A1 could promote angiogenesis, renal inflammation, and cell apoptosis to aggravate renal fibrosis induced by UUO. As an agonist of NR4A1, Cytosporone B (Csn-B) could inhibit the renal fibrosis by attenuating angiogenesis, renal inflammation and cell apoptosis. In addition, the PI3K/AKT pathway was activated with NR4A1 knockdown in vivo and in vitro experiments. In conclusion, our study demonstrates that NR4A1 can ameliorate renal fibrosis. Furthermore, we speculate that its underlying mechanism may be related to the activation of PI3K/AKT pathway according to our present results.© 2024. The Author(s).