Perpyrrospirone A (1) characterized an unprecedented 6/5/6/8/5/13/6 oxahexacyclic scaffold with a unique peroxide-bridged 8,9-dioxa-2-azaspiro[4.7]dodecane core from marine-derived Penicillium citrinum. Compounds 2 and 3 possessed rare oxatetracyclic (6/5/6/5) skeleton fused with a 13-menbered-ring macrocyclic moiety. Their structure and absolute configurations were determined by comprehensive spectroscopic analyses, ECD data coupled with TD-DFT calculations and X-ray diffraction experiments. In addition, 7 showed cytotoxicity and induced apoptosis of Hela cells in a dose-dependent manner after a 48 h treatment.