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 ( 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.