Utilize Metabolomics Molecular Networking to Guide the Discovery of Chemical Entities from Cordyceps militaris Against Blue Light Hazards.

Increasing exposure to blue light has raised concern about retinal injury, particularly in retinal pigment epithelial (RPE) cells. N-retinylidene-N-retinylethanolamine (A2E), a photosensitive fluorophore associated with age-related macular degeneration, is an important mediator of this process. In this study, feature-based molecular networking guided the identification of cordylutenes A-J (1-10), a new molecular family of blue light-protective fungal pigments from Cordyceps militaris. These metabolites possess a previously unreported symmetric all-E C20 polyene dicarbonyl skeleton with carotenoid-like UV absorption. They were characterized at the molecular-family level by shared UV features and diagnostic, internally consistent MS2 fragmentation patterns. Cordylutenes A (1) and B (2) were isolated as representative members for structural characterization. In an A2E-mediated blue-light injury model in ARPE-19 cells, the cordylutene complex (CCL, 1 μg/mL) and cordylutene A (1, 0.1 μg/mL) improved cell viability to 84.78 ± 4.02% and 92.14 ± 1.88%, respectively, and reduced intracellular oxidative stress to 63.67 ± 3.33% and 43.89 ± 9.59%, respectively. These findings identify cordylutenes as a new family of fungal pigments with protective effects in an A2E-mediated photo-oxidative retinal cell injury model.