Marine-Derived Polyketides from <i>Penicillium</i> sp. Enhance Cutaneous Wound Healing through Metabolic and Regenerative Signaling

High Resolution Image Download MS PowerPoint Slide Marine-derived fungi represent a rich yet underexplored source of bioactive secondary metabolites with therapeutic potential. In this study, we isolated and characterized five polyketide compounds from the marine-derived fungus Penicillium sp. SG-W3 and investigated their wound healing activities and underlying molecular mechanisms. At noncytotoxic concentrations, the isolated polyketides significantly enhanced keratinocyte wound closure and three-dimensional spheroid formation in HaCaT cells. These effects were accompanied by increased expression of regenerative markers, including CD44 and ALDH1, and pronounced metabolic modulation characterized by elevated glycolytic activity, enhanced mitochondrial respiration, and upregulation of key metabolic regulators such as GLUT1, HK2, LDHA, PKM2, and PGC-1α. Among the tested compounds, penimethavone A and endocrocin exhibited the most potent biological activities. In a murine full-thickness excisional wound model, topical application of the polyketides significantly accelerated wound closure and enhanced wound repair. Immunoblot analyses of wound tissue lysates demonstrated increased expression of total-AKT, α-smooth muscle actin, ALDH1, and HK2, supporting enhanced regenerative signaling and metabolic activation in vivo . Computational predictions point toward a possible involvement of PI3K–AKT-related pathways. Collectively, these findings demonstrate that marine-derived polyketides from Penicillium sp. SG-W3 promote cutaneous wound healing by enhancing keratinocyte motility, metabolic adaptability, and regenerative signaling, highlighting their potential as pharmacologically active natural compounds for the treatment of impaired wound repair.