Phytochemical Analysis and Phytometabolomic Profiling of Ficus lindsayana Leaf Extract with Evaluation of Antioxidant, Anti-Inflammatory, Cyto- and Genotoxic Activities

Ficus lindsayana is recognized for its medicinal properties, with previous studies highlighting the antioxidant and anti-inflammatory effects of its latex (FLtA) and root (FRE) extracts. Harvesting these plant parts, however, raises ecological concerns. This study evaluates the phytochemical profiles, safety, and biological activities of F. lindsayana leaf (FL) extracts as more sustainable alternatives. Leaves were extracted using hot water (FLA) and 80% ethanol (FLE), yielding 32.9% and 11.4%, respectively. Metabolomic and targeted HPLC-MS/MS analyses revealed distinct phytochemical compositions. FLE was enriched in flavonoid aglycones and lipophilic compounds, while FLA contained higher levels of polar phenolics. FLA showed greater total phenolic and flavonoid contents and stronger antioxidant activity, with an SC50 of 159 μg/mL for the DPPH assay. In contrast, FLE demonstrated more pronounced anti-inflammatory activity. In LPS-stimulated RAW 264.7 macrophages, FLE significantly reduced nitric oxide production and iNOS expression at both the protein and mRNA levels. FLE also reduced IL-6 secretion in a dose-dependent manner without affecting TNF-α, suggesting selective cytokine modulation. Both extracts exhibited low cytotoxicity (IC20 > 800 µg/mL in most cell types), non-hemolytic properties, and no mutagenic activity in the Drosophila wing spot assay. Compared to root and latex extracts, FLE ranked second in anti-inflammatory potency (FRE > FLE > FLA = FLtA). FLE, therefore represents a promising candidate, combining potent bioactivity with environmental responsibility and supporting the further development of F. lindsayana leaf-derived products for use in functional foods or botanical therapeutics.