Flavonoid–Sesquiterpenoid Hybrids from the Leaves of <i>Syzygium simile</i> and Their Anti-Lipid Droplet Accumulation Activities

Metabolic-associated fatty liver disease (MAFLD) represents a spectrum of hepatic disorders characterized by excessive lipid accumulation in the liver with a global prevalence rate of 30%. Despite their increasing prevalence, current therapeutic interventions remain suboptimal, constrained by substantial adverse effects and prohibitive treatment costs. Through an anti-lipid droplet (LD) accumulation screening platform, over 3000 methanolic extracts of Formosan plants were evaluated. Among them, the leaf extract of <i>Syzygium simile</i> demonstrated significant inhibitory activity of 40% at 25 μg/mL, emerging as the most promising species. Through bioassay-guided fractionation, 20 compounds were isolated from the <i>n</i>-hexane layer of the leaves, including nine new compounds [simisyzygins C-G (<b>1</b>-<b>5</b>, respectively) and simicadinenes A-D (<b>6</b>-<b>9</b>, respectively)] and 11 known compounds. These new compounds possess unique carbon skeletons characterized as flavonoid-sesquiterpenoid hybrids. Their structures were elucidated by the analysis of spectroscopic data. The structures of <b>1</b>, <b>4</b>, <b>5</b>, and <b>11</b> were further confirmed by single-crystal X-ray diffraction analysis. Syzygioblane B (<b>11</b>) demonstrated the most potent inhibition of LD accumulation in Huh7 cells, achieving a 64.1% reduction at 40 μM with dose-dependency (5-40 μM) and no observable cytotoxicity. This is the first phytochemical and biological investigation of <i>S</i>. <i>simile</i> that highlights its potential as a promising botanical drug candidate for treating LD accumulation-related diseases.