ETHNOPHARMACOLOGICAL RELEVANCE: Microangiopathy represents a critical pathological characteristic of lupus nephritis (LN), with steroid resistance (SR) frequently observed among patients. Panax notoginseng saponins (PNS) has demonstrated potential in mitigating P-glycoprotein (P-gp)-mediated SR and attenuating inflammatory damage in glomerular endothelial cells (GECs) through exosomal pathways, although the precise mechanisms underlying these effects have yet to be fully elucidated. AIM OF THE STUDY: This research examines the impact of PNS on microangiopathy in steroid-resistant lupus nephritis (SR LN) and explores its involvement in the mitochondrial autophagy-NLRP3 inflammasome pathway mediated by exosomes. MATERIALS AND METHODS: Steroid-resistant models were developed using methylprednisolone (MPS) in murine peritoneal macrophages (Mø). Exosomes were characterized, and biochemical markers of lupus nephritis (LN) were evaluated. Renal pathological alterations were analyzed using hematoxylin and eosin (H&E), Masson's trichrome, and periodic acid-Schiff (PAS) staining. Mitochondrial autophagy was assessed through transmission electron microscopy. Apoptosis, mitochondrial membrane potential (MMP), P-glycoprotein (P-gp), Rhodamine-123 (Rh-123), and reactive oxygen species (ROS) were measured using flow cytometry. The expression of MDR1, PINK1/Parkin, and NLRP3 at the protein and gene levels was determined via immunoblotting and real-time PCR. RESULTS: Exosomes derived from SR Mø increased the expression of MDR1 and P-glycoprotein (P-gp) in GECs, reduced Rhodamine 123 (Rh-123) accumulation, inhibited mitochondrial autophagy, and activated the NLRP3 inflammasome, thereby exacerbating renal inflammation and tissue damage. Conversely, PNS were found to lower the levels of pro-inflammatory cytokines, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interleukin-18 (IL-18), and interleukin-1 beta (IL-1β). PNS also decreased P-gp expression and increased Rh-123 accumulation. Furthermore, PNS downregulated cleaved-Caspase1 while upregulating PINK1, Parkin, Beclin-1, and the ratio of LC3II/LC3I. This dual effect of PNS reversed SR and improved renal inflammation damage. CONCLUSION: PNS demonstrated an improvement in renal function and a reduction in histopathological damage, suggesting its potential therapeutic applications for LN.