Diverse metabolites with anti-psoriasis potential from different fermentations of the fungicolous fungus Xylaria longipes HFG1018

The genus <i>Xylaria</i> is a promising source of bioactive compounds. This study examined the diversity of secondary metabolites (SMs) in <i>Xylarialongipes</i> under three fermentation conditions, resulting in the isolation of 14 new SMs and 27 known ones. The structures, including absolute configurations, were determined using NMR spectroscopy, HRESIMS analysis, and computational methods (ECD, ¹³C NMR data, and optical rotation). A comprehensive library of SMs was established, enabling metabolomics-wide association studies that identified culture conditions as a key factor influencing SM production. This compound library also facilitates the determination of absolute configurations for diplosporins by analyzing <i>J</i> values and CD trends. Anti-proliferative tests against induced T/B lymphocytes and HaCaT cells revealed that over half of the compounds exhibited significant inhibitory activity, with compounds <b>2</b>, <b>15</b>, and <b>32</b> reducing IFN-<i>γ</i> secretion. Compound <b>32</b> demonstrated promising anti-psoriatic effects by inhibiting NF-<i>κ</i>B p65 phosphorylation in HaCaT cells. This initial systematic chemical study of <i>X.longipes</i> under different conditions provides insights into structure-activity relationships.