A novel sesquiterpene methylcyclopentenedione, penicilliumin B (1), was obtained from a deep sea-derived fungus Penicillium sp. F00120, together with three known sesquiterpene cyclohexenones (2-4). Penicilliumin B (1), presenting the first example with the sesquiterpene cyclopentenedione skeleton as natural products, was structurally determined by analysis of the NMR and MS spectroscopic data, while the absolute configurations were assigned by single-crystal X-ray experiments. The plausible biosynthetic pathway of the unusual cyclopentenone skeleton of 1 was proposed. Penicilliumin B (1), with low toxicity, was showed significant potential to inhibit the kidney fibrogenic action in vitro, by a mechanism dependent on disruption of oxidative stress, presenting a new type of promising renoprotective agent.