Abstract
Background: The SRY-related HMG-box (SOX) transcription factor family comprises 20 master regulators governing cell fate determination, stem cell pluripotency, and lineage-specific differentiation—processes fundamental to regenerative medicine. Notably, SRY-related HMG-box 2 (SOX2 ) serves as one of the four Yamanaka factors essential for induced pluripotent stem cell (iPSC) generation, while SOX17 directs definitive endoderm specification critical for hepatocyte and pancreatic β-cell derivation. Despite their therapeutic promise, pharmacological approaches capable of coordinately modulating multiple SRY-related HMG-box genes(SOX) for in vivo cellular reprogramming remain elusive.
Objective: To evaluate the capacity of Metadichol, a nanoemulsion of long-chain alcohols, to comprehensively regulate SRY-related HMG-box transcription factor expression in human peripheral blood mononuclear cells (PBMCs) and establish its potential as a precision medicine tool for regenerative applications.
Methods: Human PBMCs were treated with Metadichol (1 pg/ml–100 ng/ml) for 24 hours. Expression of 20 SOX family genes was quantified by qRT-PCR. Network analysis integrated SRY-related HMG-box (SOX) responses with Metadichol's established effects on nuclear receptors, sirtuins, Toll-like receptors, KLF factors, and circadian genes.
Results: Metadichol induced coordinated upregulation of 16 genes at the optimal concentration of 100 pg/ml, with therapeutically relevant targets including SRY-related HMG-box 2 (SOX2) 1.72-fold; SRY-related HMG-box 17 (SOX17) (3.45-fold; endoderm/metabolic), SRY-related HMG-box 4 (SOX4 ) (3.46-fold; lymphopoiesis/ cardiac), SRY-related HMG-box 10 (SOX10) (3.80-fold; neural crest/oligodendrocytes), and SRY-related HMG-box 7 (SOX7) (3.37-fold; vascular specification). Strong correlations between functionally related SRY-related HMG-box (SOX) genes (r = 0.76–0.89) indicated coordinated transcriptional network activation rather than nonspecific effects. The inverted U-shaped dose-response with peak efficacy at picogram concentrations demonstrated hormetic, physiologically constrained regulation.
Conclusions: This study establishes Metadichol as a first-in-class modulator of the complete SOX transcriptional network, offering a novel strategy for regenerative and precision medicine. Unlike conventional iPSC-based therapies requiring ex vivo genetic manipulation, Metadichol enables in vivo transcriptional reprogramming of endogenous cell populations through coordinated activation of pluripotency SRY-related HMG-box 2(SOX2), differentiation SRY-related HMG-box 19 and 19 (SOX17, SOX9), and tissue-specific regeneration programs SRY-related HMG-box 4,7 and 10 (SOX4, SOX7, SOX10). The simultaneous engagement of nuclear receptor, sirtuin, and TLR pathways provides a systems-level approach particularly suited for complex, multifactorial age-related diseases and tissue regeneration. Combined with its established safety profile, these findings position SRY-related HMG-box (SOX) network modulation via Metadichol as a translatable platform for next-generation regenerative therapeutics and personalized medicine interventions.