Trichodenoids A and B, Two Skeletally Unprecedented Polyketides from <i>Trichoderma reesei</i> with Cardioprotective Effects against H₂O₂-Induced Injury

<i>Trichoderma reesei</i>, recognized by the FDA as a food-safe strain, plays a vital role in food fermentation. Although the enzymatic applications of <i>T. reesei</i> are well-established, the health benefits of its fermentation-derived metabolites are yet to be fully explored. Trichodenoids A (<b>1</b>) and B (<b>2</b>), two skeletally unprecedented polyketides, were isolated from the endophytic fungus <i>T. reesei</i> originating from the plant <i>Gastrodia elata</i> Blume. Their structures were elucidated via spectroscopic data, single-crystal X-ray crystallographic analysis, quantum chemical DP4+ analysis, and ECD calculation. Compounds <b>1</b> and <b>2</b> were uniquely defined by the unusual 6/6/5 and 6/6/5/6 ring systems, respectively, which were proposed to be formed through key Diels-Alder and Baeyer-Villiger reactions during biosynthesis. Compound <b>2</b> had the potential to mitigate H₂O₂-induced oxidative stress in H9C2 cells by reducing intracellular ROS levels, restoring mitochondrial function, and regulating the mRNA expression related to oxidative stress, inflammation, and autophagy. These findings highlight compound <b>2</b> as a potential candidate for natural antioxidants and even as dietary supplements for cardiovascular health.