Idiopathic membranous nephropathy (IMN) belongs to an important pathogenic category of adult nephrotic syndrome. PLA2R1 exposure is critical for triggering the pathogenesis of PLA2R1-related IMN. However, the pathogenesis of IMN and the molecular mechanism of treatment remain to be further clarified. The expression changes of activated protein C (APC) and PLA2R1 in IMN patients were quantified by qPCR. A zymosan activated serum (ZAS)-induced IMN podocyte model was established in vitro. Podocyte apoptosis was detected via flow cytometry and caspase‑3 assay. The expression levels of APC, p-ERK1/2, ERK1/2, YB-1 and PLA2R1 were detected by western blotting. The regulation relationship between YB-1 and PLA2R1 was detected by dual fluorescent reporter system. In IMN patients, the expression level of PLA2R1 was increased, whereas the expression level of APC was decreased. When APC was added to podocytes in vitro, the phosphorylation of ERK1/2 was increased, which could promote the translocation of YB-1 to the nucleus that reduces the expression of PLA2R1 at the cellular transcriptional level, thereby inhibiting podocyte apoptosis. Our study is the first to report that APC can improve membranous nephropathy by affecting podocyte apoptosis through the ERK1/2/YB-1/PLA2R1 axis. This study will provide a new targeted therapy for IMN patients with high PLA2R1 expression.