Dr. Weeks’ Comment: Mentors have been so helpful to me over my career. Recently, I’ve become friends with a great guru of melatonin, Russell Reiter. I am indebted to him as are my patients who have benefited from high dose melatonin. This is an inspirational man who is highly productive today in his 90s . He’s the scientist who really taught the world the benefits of high dose melatonin (60-180mg) for neuro-protective and anti-cancer properties. Here below we find his very detailed and elegant biochemical description of the anti-cancer properties of melatonin.
Volume 78, Issue 4 e70156
REVIEW
Multiaxial Biophysical Control of Oncogenic Phase Separation by Indoleamines: A Proof-of-Concept Synthesis of Landscape-Level Regulation
ABSTRACT
Oncogenic condensates act as biophysical sanctuaries that stabilize malignant survival programs. However, a universal regulator capable of orchestrating the integrated biophysical axes governing cellular phase behavior has remained elusive. Here, we introduce a sovereign singularity framework, presenting a deductive biophysical model that positions the indoleamine melatonin as a master regulator of biological phase separation. A systematic synthesis and integrative bioinformatics analysis were performed to identify the intersection between melatonin-responsive genes and the phase-separation proteome. We identified a core 26-gene regulatory signature—including AR, BCL2, CGAS, CTNNB1, EP300, EZH2, EGFR, IKBKG (NEMO), KEAP1, KDM1A (LSD1), LEF1, MYC, NANOG, PRNP (PRPc), SMAD3, SOX9, SQSTM1, TFEB, TFAM, TP53, TWIST1, USP10, WWTR1 (TAZ), VIM, YAP1, and YTHDF3—at the intersection of melatonin signaling and condensate architecture. We propose that melatonin utilizes a tri-lever framework of redox tuning (Lever I), multivalent plasticization (Lever II), and dielectric recalibration (Lever III) to render oncogenic programs biophysically untenable. This model provides a mechanical basis for high-resolution regulatory outcomes that modulate the organizational logic of nuclear decision-making (Axis I), state-transition (Axis II), and stress-adaptation (Axis III) condensates. Our results define a strategic platform for disrupting condensate-driven malignancy through the systemic modulation of the cellular biophysical landscape.