Psoriasis is a chronic immune-mediated inflammatory skin disease and the TNF-alpha is an important therapeutic target of this disease. In our continuous study of bioactive natural products from fungi, the first ergosterol-polyether adducts, polyaspers A (1) and B (2), along with two known ergosterols, (3 beta,5 alpha,6 alpha,22E)-5,6-epoxy-3-hydroxyergosta-8,22-dien-7-one (3) and calvasterol B (4), were isolated from Aspergillus sp. TJ507. Structure elucidation was accomplished by extensive spectroscopic analysis and single-crystal X-ray diffraction tests. Polyaspers A and B possessing an unequalled 6/6/6/5/5/6/6/6/6 nonacyclic system, and their biosynthetic pathways were proposed to include intermolecular cyclization and Diels-Alder reactions. Activity screen of these isolates showed that 1-3 could improve the cell viability in an actinomycin D/TNF-alpha induced L929 cells death model, with the EC50 values of 49.85, 46.75 and 4.99 mu mol/L, respectively, and the activity of 3 was even comparable with that of the positive control SPD304. Further bioactive investigations discovered 3 could suppress the inflammatory response simulated with TNF-alpha in HaCaT cells. In an imiquimod-induced psoriasis murine model, 3 significantly restrained the development of psoriasis symptoms and reduced the expression of IL-17 and IL-23, presenting an anti-psoriatic effect. As such, those ergosterol derivatives, might serve as lead compounds for the development of novel TNF-alpha inhibitory agents in the clinical treatment of psoriasis.