Metadichol Modulates the DDIT4-mTOR-p70S6K Axis: A Novel Therapeutic Strategy for mTOR-Driven Diseases

This work explores the intricate functions of mTOR and its downstream effector p70S6K in human health and disease. mTOR, a highly conserved serine/threonine kinase, serves as a central signaling hub integrating various cellular processes. Its dysregulation is implicated in numerous human diseases, highlighting its importance in cellular homeostasis. p70S6K, a crucial downstream target of mTOR, plays a vital role in mediating the effects of mTOR on protein synthesis and cell growth. DDIT4: Induced by hypoxia, DNA damage, and nutrient deprivation, DDIT4 inhibits mTOR signaling via the TSC1/TSC2 complex, which suppresses mTORC1 activity. Research has focused on metadichol, a nanoemulsion of long-chain alcohols with C28 as the primary component. Key Observations1. Metadichol increases DDIT4 expression, but mTOR and P70S6 kinase expression are downregulated. Conversely, decreases in DDIT4 are associated with increased mTOR and P70S6 kinase levels.2. The effects are consistent in PBMCs (immune cells) and various cancer cell lines (U87, A-549, MDAMB-231-HCT116, and Hep G2. The involvement of DDIT4, mTOR, and p70S6K in various physiological processes and pathological conditions, including cancer, diabetes, and aging, underscores their potential as therapeutic targets. Metadichol shows significant promise in targeting DDIT4, mTOR, and p70S6K for cancer treatment, given the crucial roles of these proteins in cancer cell growth, survival, and metastasis. Compared with most mTOR, p70S6K, and DDIT4 inhibitors described in the literature, which are active in the nanomolar to micromolar range, the activity of metadichol at 1 pg/mL (10‒12 g/mL) is exceptionally potent.Metadichol’s ability to modulate DDIT4, mTOR, and P70S6 kinase suggests that it regulates cellular growth and stress responses. In cancer, it may inhibit proliferation, while in PBMCs, it could balance immune function. These findings highlight the potential of metadichol as a therapeutic agent for the treatment of mTOR-driven diseases.