Metadichol Orchestrate Pluripotency via Nuclear Receptors during Cellular Reprogramming

Nuclear receptors (NRs) are ligand-activated transcription factors that regulate the gene expression required for cellular reprogramming and pluripotency. This study examined the role of metadichol, a nanoemulsion of long-chain lipid alcohols (C26--C30), in modulating NR expression to increase the reprogramming of induced pluripotent stem cells (iPSCs). Using a nonviral method with metadichol at concentrations ranging from 1 pg/mL to 100 ng/mL, seven cell lines were evaluated, including human mesenchymal stem cells (HMSCs), normal human dermal fibroblasts (NHDFs), HEK293 cells, HeLa cells, THP-1 cells, triple-negative breast cancer cells, and primary prostate cancer cells. To assess the expression of 49 NRs, including estrogen-related receptor beta (NR3B2), nuclear receptor subfamily group A member 2 (NR5A2), and nuclear receptor subfamily 5 group member 1 (NR5A1), which can replace Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc) during iPSC generation, quantitative real-time polymerase chain reaction and western blot analyses were employed. Normal human dermal fibroblasts (NHDFs) and human mesenchymal stem cells strongly upregulated NR5A1 and NR5A2, which supported Oct4 replacement, and ERRβ, which facilitated Klf4 substitution. This upregulation made them highly suitable for NR-mediated reprogramming. Metadichol also induced the expression of pluripotency markers (e.g., alkaline phosphatase and Yamanaka factors), sirtuins, Fox head box protein O1 (FOXO1), Klotho, telomerase transcriptase (TERT) and insulin/beta cell formation, which suggests enhanced epigenetic remodeling and cell survival. This nonviral, scalable approach positions metadichol as a promising reagent for induced pluripotent stem cell (iPSC) differentiation in regenerative medicine, particularly for diabetes and oncology. These results suggest that metadichol could act as a universal nuclear receptor ligand, suggesting a comprehensive approach for efficient and safe induced pluripotent stem cell (iPSC) reprogramming.