Effects of a Cyclodipeptide-Containing Extract from Marine Penicillium chrysogenum Against Oxidative, Inflammatory and UV-Induced Damage on Human Keratinocytes

Skin photoaging and chronic inflammation are primarily driven by ultraviolet (UV) radiation and oxidative stress, which activate pro-inflammatory cytokine cascades and promote cellular senescence. Marine-derived fungi represent a rich yet underexplored source of bioactive secondary metabolites with potential stress-modulating properties. This study characteriseda cyclodipeptide-containing n-butanol extract (PC_BuOH) from Penicillium chrysogenum isolated from seawater collected off the coast of Corigliano (Calabria, Italy) and evaluated its cytoprotective effects on HaCaT human keratinocytes exposed to oxidative (H2O2), inflammatory (LPS), and UV-mediated stress. Chemical profiling by UHPLC-DAD-HR-Orbitrap/ESI-MS allowed the tentative annotation of eighteen metabolites, twelve of which were classified as cyclodipeptides (2,5-diketopiperazines).. The extract was statistically non-cytotoxic up to 100 µg/mL. Biological activity was assessed using pre- and post-treatment protocols by measuring cell viability (MTT), intracellular reactive oxygen species (ROS) levels (DHE staining), SA-β-galactosidase positivity, and IL-1β and IL-6 secretion (ELISA). Pre-treatment with PC_BuOH (1–10 µg/mL) significantly reduced H2O2-induced ROS accumulation and SA-β-gal positivity, and attenuated LPS-induced cytokine release. In contrast, protection against UV-induced damage was more evident under post-treatment conditions, where the extract decreased SA-β-gal positivity and cytokine secretion following irradiation. Overall, PC_BuOH showed antioxidant activity and reduced cytokine release and SA-β-gal positivity under the tested conditions. These findings highlight marine fungal cyclodipeptides as promising candidates for dermatological strategies targeting photoaging and cutaneous inflammation.