Penichrysosterol, a novel dual inhibitor of ferroptosis and neuroinflammation from the deep-sea fungus Penicillium chrysogenum.

Neurodegenerative diseases are driven by a self-amplifying loop of neuroinflammation and ferroptosis. Current therapeutic strategies, however, are limited by their inability to achieve dual-pathway inhibition. Thus, there is an urgent need for multi-target agents capable of concurrently mitigating both processes. In this study, chemical investigation of the deep-sea-derived fungus Penicillium chrysogenum C7 afforded thirteen compounds, including a new ergostane-type steroid (1), named penichrysosterol, and a new 3,5-dimethylorsellinic acid derived meroterpenoid (2). The structures of 1 and 2 were determined by extensive spectroscopic analysis and by comparison of the experimental and calculated 13C NMR and ECD data. The α-hydroxy-α,β-unsaturated ketone moiety at C-5-C-7 in 1 is scarcely found in steroids. Compound 2 was the second example bearing a 3,6,7,10-tetramethyl-2-oxaspiro[4.5]deca-6,8-diene-1,4-dione unit in nature. Penichrysosterol (1) was identified as a promising dual-function agent, exhibiting potent inhibitory activities against both RSL3-induced ferroptosis and neuroinflammatory responses in BV2 microglia with EC50 values of 4.82 μM and 2.52 μM, respectively. Mechanistically, 1 significantly suppressed ferroptosis by reducing lipid peroxidation and glutathione depletion, while restoring the expression of GPX4 and SLC7A11 via activation of the Nrf2 pathway. Simultaneously, it attenuated neuroinflammation by inhibiting NF-κB activation and subsequent release of pro-inflammatory cytokines such as IL-1β and IL-6. These findings suggest that 1 is a dual-acting lead compound for the development of neurodegenerative disease therapies.