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. The online version contains supplementary material available at https://doi.org/10.1007/s42995-026-00385-2.
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