Anti-inflammatory geranylated isoflavones from the roots of Ficus cyathistipula – a species with untapped potential

As a part of an ongoing investigation of the phytochemical profile of unresearched Ficus species, an ethanolic extract of the roots of F. cyathistipula was subjected to extensive separation, leading to the isolation of twelve prenylated and geranylated (iso)flavonoids, including four novel geranylated isoflavones ( 1–4 ) and a novel geranylated dihydroflavonol ( 5 ). The structures of the isolated compounds were elucidated using NMR, HRMS, and ECD data. All isolates ( 1 – 12 ) were evaluated for anti-inflammatory potential by assessing their effects on four transcription factors (NF-κB, Nrf2, PPARγ, and AhR) and for antioxidant activity in vitro. Eight compounds ( 1 – 6 , 9 , and 12 ) significantly suppressed NF-κB activity in lipopolysaccharide-stimulated THP1-Blue NF-κB monocytes, with effects comparable to or exceeding prednisolone at the same concentration. The most effective compounds, 4 and 9 , also attenuated NF-κB nuclear translocation and significantly reduced TNF-α mRNA levels, while compound 9 additionally decreased IL-1β mRNA levels in THP1-Blue NF-κB-derived macrophages. The strongest antioxidant effect was exhibited by compound 5 , which reduced 2,2′-azobis(2-methylpropionamidine) dihydrochloride-induced reactive oxygen species production by 20%. Compound 10 weakly antagonized 2,3,7,8-tetrachlorodibenzo- p -dioxin-induced AhR activation (30%). In summary, the first systematic phytochemical investigation of the roots of F. cyathistipula identified geranylated isoflavones as promising anti-inflammatory leads acting through NF-κB pathway modulation.