Novel prenylated diketopiperazines with anti-osteoclastogenic activity from the deep-sea-derived Penicillium limosum ZEN48

Abstract A systematic chemical investigation of the deep-sea-derived fungus Penicillium limosum ZEN48 resulted in the isolation of four new indole-diketopiperazine alkaloids, limopiperazines A–D ( 1 – 4 ), alongside 16 known analogues ( 5 – 20 ). The structures of the new compounds were determined through comprehensive spectroscopic analysis, quantum chemical calculations, X-ray crystallography, and biogenetic considerations. Limopiperazine C ( 3 ) potently inhibited osteoclast differentiation and disrupted actin ring formation. Integrated RNA sequencing, RT-qPCR and molecular docking revealed that limopiperazine C exerts the anti-osteoclastogenic effect by modulating the ferroptosis signaling pathway via targeting heme oxygenase-1 (Hmox-1), positioning it as a promising lead compound for developing anti-osteoporotic agents.