Chrysogenones A–E: Malonyl-Modified Ergosterone Derivatives from Deep-Sea-Derived Penicillium sp. MCCC 3A00121 as Inhibitors of Renal Fibroblast Activation

Five previously undescribed steroids, chrysogenones A-E (<b>1</b>-<b>5</b>), were isolated from the deep-sea-derived <i>Penicillium</i> sp. MCCC 3A00121. Their chemical structures were unambiguously established through comprehensive spectroscopic analyses, density functional theory (DFT)-based electronic circular dichroism (ECD) calculations, and X-ray crystallography. Chrysogenones represent a class of oxidatively modified ergosterone-type derivatives, with <b>1</b>, <b>2</b>, and <b>5</b> featuring an uncommon malonyl substitution at C-12 of the ergosterone skeleton. Biologically, <b>1</b>-<b>5</b> exhibited varying degrees of inhibitory activity against renal fibrosis, as evidenced by the downregulation of the key fibrotic markers α-smooth muscle actin (α-SMA) and collagen I (COL1A1). Among them, chrysogenone B (<b>2</b>) emerged as the most promising candidate, demonstrating superior potency and pronounced inhibition of activated NRK-49F cell proliferation. Integrated network pharmacology analysis and molecular docking studies further suggested that the anti-renal fibrotic effects of compound <b>2</b> may be mediated through its interaction with putative molecular targets, including AKT1, HSP90AA1, and MDM2.