A Marine-Derived Steroid from Rhodococcus sp., 3,12-Dioxochola-4,6-dien-24-oic Acid, Enhances Skin Re-Epithelialization and Tissue Repair.

Abstract

The discovery of bioactive natural compounds from microbes holds promise for regenerative medicine. In this study, we identified and characterized a steroid-like compound, 3,12-dioxochola-4,6-dien-24-oic acid (DOCDA), from a crude extract of Rhodococcus sp. DOCDA significantly promoted wound healing by enhancing HaCaT cell invasion and migration. It upregulated key growth factors (EGF, VEGF-A, IGF, TGF-β, and HGF), indicating the activation of regenerative signaling. Additionally, DOCDA increased the expression of genes related to focal adhesion and cytoskeletal regulation (ITGB1, ITGA4, FAK, SRC, RHOA, CDC42, RAC1, and paxillin), supporting enhanced cellular motility and remodeling. Notably, DOCDA promoted stem-like properties in HaCaT cells, as shown by increased spheroid formation and elevated levels of the stemness markers ALDH1 and CD44. Target prediction and molecular docking identified the glucocorticoid receptor (GR) as the primary target of DOCDA, with a docking score of -7.7 kcal/mol. Network and pathway enrichment analysis revealed that GR-linked pathways were significantly associated with wound healing, including steroid hormone signaling, inflammation, immune responses, and cell migration. In vivo, the topical application of DOCDA led to over 70% wound closure in mice by day 5. These findings suggest that DOCDA is a steroid-like compound that accelerates wound healing and may serve as a potential agent in regenerative therapy.