Lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE), is the leading cause of morbidity and mortality in SLE patients. Renal interstitial fibrosis drives end-stage renal failure in chronic kidney diseases, including LN. Paeoniflorin (PF), a bioactive monoterpenoid glycoside from Paeonia lactiflora, exhibits renal protective effects, but its antifibrotic mechanisms in LN remain unclear. MRL/lprmice are classic models for studying LN.

 LN was induced in MRL/lpr mice, followed by treatment with PF (25, 50, and 75 mg/kg) or vehicle for 9 weeks. Renal cortical lncRNA sequencing and molecular docking were performed to identify potential EMT-related targets. In addition, TGF‑β1‑stimulated HK-2 cells and HK-2/M2c macrophage co-culture systems were treated with PF (40, 60, and 80 μM). Assessments included renal function, histopathological changes, expression of EMT markers (E-cadherin, vimentin, α‑SMA), and activity of the TGF‑β1/Smad2/3 pathway.

LncRNA sequencing revealed 1,390 differentially expressed lncRNAs between MRL/lpr and MRL/MP mice. Molecular docking indicated strong binding affinities of PF with TGF-β1, Smad2, Smad3, E-cadherin, N-cadherin, and vimentin. PF administration significantly and dose-dependently reduced proteinuria, serum ANA, and anti-dsDNA antibody levels in MRL/lpr mice, accompanied by attenuated renal inflammatory infiltration and collagen deposition. PF upregulated E-cadherin while downregulating vimentin and α‑SMA expression in renal tissues. In vitro, PF reversed TGF-β1-induced EMT in HK-2 cells and HK-2/M2c co-cultures and suppressed activation of the TGF-β1/Smad2/3 signaling pathway.

PF attenuates renal fibrosis in lupus nephritis (LN) by suppressing the TGF‑β1/Smad2/3 signaling pathway, thereby inhibiting epithelial‑mesenchymal transition (EMT). This disruption of EMT reduces the accumulation of extracellular matrix components such as collagen I and fibronectin, which are key drivers of interstitial fibrosis and progressive kidney dysfunction. By targeting this core fibrotic cascade, PF not only mitigates structural damage but also preserves renal function in the context of LN. These findings position PF as a promising therapeutic candidate, offering a potential strategy to overcome the limitations of current immunosuppressive therapies that lack direct anti‑fibrotic effects.