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Background/Objectives: Neuroinflammation is a key contributor to neurodegenerative diseases. Magnolia liliiflora Desr. is a traditional medicinal plant with therapeutic potential; however, its bioactive constituents and mechanisms remain unclear. This study aimed to identify active compounds from M. liliiflora leaves that inhibit inflammatory responses in microglial BV-2 cells. Methods: Anti-inflammatory activity was assessed by measuring nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. UPLC–qTOF MS/MS-based metabolite profiling combined with bioactivity-guided analysis was used to identify candidate biomarkers, which were subsequently isolated and structurally characterized. Network pharmacology and molecular docking analyses were performed to predict potential molecular targets and mechanisms of action. The effects on NF-κB signaling and inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression were further validated by Western blot analysis. Results: Two previously undescribed lignans (1 and 2) and five known lignan derivatives (3–7) were isolated from the leaves of M. liliiflora. At 20 µM, compounds 1, 3–5, and 7 exhibited moderate inhibitory effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated BV2 microglial cells, with 23%, 33%, 69%, 56% and 49% inhibition, respectively, and no detectable cytotoxicity. Notably, an ethyl acetate-derived enriched subfraction showed 97% inhibition of NO production at 10 µg/mL, suggesting potential synergistic activity of M. liliiflora lignans. Network pharmacology and molecular docking analyses predicted interactions between the isolated lignans and NF-κB pathway-related targets, thereby guiding subsequent experimental validation. Both compounds significantly reduced the expression of iNOS and COX-2 and suppressed LPS-induced activation of the NF-κB signaling pathway in a concentration-dependent manner, as confirmed by Western blot analysis. Overall, the results demonstrate that M. liliiflora leaves are a source of bioactive lignans that attenuate microglial activation by inhibiting NO production and key inflammatory mediators, effects that are associated with the suppression of the NF-κB signaling pathway. Conclusions: This study identified bioactive lignans from M. liliiflora leaves and demonstrated their anti-inflammatory activity in microglial cells. The findings establish the structural identities of the active compounds and confirm that M. liliiflora leaves are a valuable source of lignans with therapeutic potential for neuroinflammatory and neurodegenerative disorders.
Ponce‐Zea et al. (Fri,) studied this question.