Multiaxial Biophysical Control of Oncogenic Phase Separation by Indoleamines: A Proof-of-Concept Synthesis of...

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 (PRP^c), 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.