<i>Polygonum cognatum</i> Extract: Multitarget Anti‐inflammatory, Antidiabetic, and Epigenetic Modulation Properties

Polygonum cognatum (Madımak) is a plant traditionally consumed for medicinal purposes in Turkey. Unlike previous studies examining samples from different regions and seasons, this research presents the first comprehensive characterization of P. cognatum collected from the Central Black Sea Region (Tokat, 40°01'02″N, 36°28'15″E; 1210 m altitude) during the vegetative growth phase (June 2024), where geographical origin and collection time significantly influence secondary metabolite profiles. This study evaluates the phytochemical profile and multitarget biological activities of P. cognatum extracts obtained using solvents of different polarities (hexane, ethanol, and water). Advanced analytical techniques (liquid chromatography-tandem mass spectrometry, high-performance liquid chromatography-diode array detector, and gas chromatography-mass spectrometry) identified 28 phenolic compounds, with the ethanol extract showing the highest diversity (24 compounds) and total phenolic content (78.6 ± 2.3 mg GAE/g). Compounds identified for the first time in P. cognatum include isoquercetin-3-O-rhamnoside, apigenin-7-O-glucoside, and luteolin-4'-O-glucoside. The ethanol extract demonstrated superior multitarget bioactivity: potent antioxidant activity ( 2,2-diphenyl-1-picrylhydrazyl (DPPH) IC₅₀: 76.4 ± 2.1 μg/mL), moderate but selective anti-inflammatory effects (COX-2 IC₅₀: 145.3 ± 5.2 μg/mL; selectivity index: 2.06, indicating preferential COX-2 inhibition over COX-1) and significant antidiabetic potential (α-amylase IC₅₀: 89.3 ± 3.1 μg/mL; α-glucosidase IC₅₀: 76.8 ± 2.9 μg/mL), and antimicrobial activity (MIC: 62.5 μg/mL against S. aureus). Notably, this study demonstrates for the first time the histone deacetylase (HDAC) inhibitory activity of P. cognatum (IC₅₀: 92.4 ± 3.8 μg/mL), revealing novel epigenetic modulation properties. Molecular docking studies showed strong correlations between binding affinities and experimental IC₅₀ values (r = -0.87 to -0.91; p < 0.01). Cytotoxicity evaluation showed favorable safety profiles (CC₅₀ > 500 μg/mL). Docking, IC₅₀, and compositional data consistently indicate that quercetin, rutin, chlorogenic acid, and kaempferol are key contributors to the observed antioxidant, antidiabetic, anti-inflammatory, and HDAC inhibitory effects. These findings establish P. cognatum as a promising multitarget therapeutic agent with novel epigenetic regulatory mechanisms, supporting its potential development for inflammatory, metabolic, and epigenetic-related disorders.