Hydroxychloroquine (HCQ) has recently been reported to be an effective treatment for IgA nephropathy (IgAN); however, the exact mechanism remains elusive. This study aimed to explore the molecular mechanisms of HCQ against IgAN. IgAN-related genes and HCQ target sets were screened from online databases, and a section of them was identified as targets of HCQ against IgAN. In total, 1575 IgAN- related genes, 415 HCQ targets, and 125 targets of HCQ against IgAN were identified. The results of the enrichment analysis showed that the targets of HCQ against IgAN were related to inflammation and immune response related pathways. The PPI network and subnetworks identified prostaglandin-endoperoxide synthase 2 (PTGS2) as the main seed gene. Molecular docking and molecular dynamic (MD) simulations revealed that HCQ could well bind to the PTGS2 protein. Furthermore, clinical data indicated that PTGS2 was overexpressed in patients with IgAN and was negatively correlated with estimated glomerular filtration rate (eGFR). Moreover, consistent with the effect of meloxicam, a PTGS2 inhibitor, HCQ could decrease the expression of PTGS2 and profibrotic proteins in the IgAN cell model. Consequently, HCQ can mediate inflammation and immune response regulation via multiple pathways and targets, among which PTGS2 is probably the key target of HCQ against IgAN.© 2025 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.