Drimane-Pyrone-Type Meroterpenoids and Co-Isolated Compounds from the Deep-Sea Fungus Penicillium rubens MABC05 and Their Anti-Ferroptotic and Cytotoxic Activities.

Ferroptosis is a critical driver of tubular necrosis, and its effective inhibition holds significant potential for mitigating renal injury. In this study, chemical investigation of the strain Penicillium rubens MABC05 yielded nine drimane-pyrone-type meroterpenoids (1-9), including six previously undescribed analogues, a previously undescribed tetrahydroxanthone-ergosterol hybrid (10), four steroids (11-14), and three xanthone derivatives (15-17). Their structures were elucidated via comprehensive spectroscopic analysis, supported by single-crystal X-ray diffraction (Mo Kα for 1 and 3, and Cu Kα for 6) and 13C NMR calculations (2 and 10). The absolute configurations of 1-5 and 10 were assigned by ECD calculation. Compounds 1-6 represent a rare group of meroterpenoids containing a fused drimane-type sesquiterpene and pyrone skeleton. Additionally, two storage-induced oxidative artifacts of 10 were also characterized. These compounds were evaluated for anti-ferroptotic and cytotoxic activities. Compound 15 exhibited inhibition against RSL3-induced ferroptosis in human renal proximal tubular epithelial cells with an EC50 value of 12.8 μM; it effectively reduced MDA levels, elevated GSH content, and suppressed lipid radical generation. Compounds 11 and 16 exhibited cytotoxicity against MCF-7 cells with IC50 values of 4.3 and 8.4 μM, respectively. Compound 15 represents a promising chemotype for ferroptosis inhibitors with potential for mitigating renal tubular injury.