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Lignan-rich beans, nuts, and various seeds are the main protective food with antioxidative and hormones modulating activity. However, although the role of lignans in mediating hormone-dependent cancers, and cardiovascular disease is well characterized, the function of lignans in anti-arthritic activity and its actual mechanisms remain unknown. A set of three new lignan derivatives named (-)-nortrachelogenin, trachelogenin, and matairesinol were extracted from Loranthus parasiticus. After the establishment of collagen-induced arthritis (CIA) model by intradermal injection of collagen, rats were treated with the mixed three new lignan derivatives ((-)-nortrachelogenin: 37%; trachelogenin: 27%; matairesinol: 25.7%) at a concentration of 50 mg/kg and 100 mg/kg, or methotrexate of 0.3 mg/kg. The mixed lignan derivatives significantly attenuated the immune responses in the joints of CIA rats, resulting in decreased levels of pro-inflammatory cytokine (IL-6, TNF-α) and boosted free androgen in serum compared to the CIA model. The results of molecular docking via the AutoDock Vina showed that lignan derivative (-)-nortrachelogenin is the most effective compound for binding to SHBG, then leading to inhibiting the activity of NFκB in LPS-stimulated macrophages. In this study, (-)-nortrachelogenin was identified as the previously unrecognized anti-inflammatory activity of natural lignan new derivative, and its molecular mechanism is related to the regulating NFκB/SHBG pathway. Our findings suggest further application of sex hormone-like compounds in treating rheumatoid arthritis and potential clinical applications of (-)-nortrachelogenin.