BACKGROUND: Aristolochic acids (AAs)-containing herbs have been used as medicinal remedies for thousands of years. However, exposure to AAI and AAII increases the risk of nephropathy and cancers. Our previous study identified AAIVa, an analogue without carcinogenicity or nephrotoxicity, exerted anti-inflammatory effects. PURPOSE: To explore AAIVa's anti-inflammatory mechanisms and assess its therapeutic potential in arthritis. METHODS AND RESULTS: In this study, we employed in vitro assays on RAW 264.7 cells and explored the underlying mechanisms of AAIVa's anti-inflammatory effect through transcriptome analysis, identifying macrophage polarization-associated genes, IL-17 signaling, and Rheumatoid Arthritis (RA) pathway. Also, we used BALB/cAnSmoc-Zap70 CONCLUSION: We provide first evidence that AAIVa exerts anti-arthritis effects, likely through modulation of macrophage polarization and restoration of the Th17/Treg balance. Our findings highlight AAIVa's mechanism of action and AAIVa's potential as a therapeutic candidate for autoimmune arthritis.