Multiaxial Biophysical Control of Oncogenic Phase Separation by Indoleamines: A Proof-of-Concept Synthesis of Landscape-Level Regulation

Background Phase-separated oncogenic condensates act as biophysical sanctuaries, stabilizing transcriptional and survival programs to drive cancer progression. While individual proteins within these assemblies are well-documented, a universal regulator capable of orchestrating the integrated biophysical axes governing cellular phase behavior has remained elusive. We propose a paradigm of landscape-level regulation mediated by the indoleamine scaffold.

A systematic synthesis and integrative bioinformatics analysis were performed to identify the intersection between melatonin-responsive genes and the phase-separation proteome. A gene set of 121 phase separation-related molecules was validated via PhaSepDB and intersected with 134 melatonin-modulated genes identified across diverse cancer models. Clinical relevance was assessed using TCGA survival datasets.

We identified a conserved network of 26 core genes—including AR, BCL2, CGAS, CTNNB1, EP300, EZH2, EGFR, IKBKG (NEMO), KEAP1, KDM1A (LSD1), LEF1, MYC, NANOG, PRNP, SMAD3, SOX9, SQSTM1, TFEB, TFAM, TP53, TWIST1, USP10, WWTR1 (TAZ), VIM, YAP1, and YTHDF3—at the intersection of melatonin signaling and PS architecture. Network analysis revealed high-confidence interactions predominantly localized to the nucleoplasm and stress granules. Melatonin significantly suppressed the majority of these oncogenic drivers, targeting pathways associated with EMT, glycolysis, and hypoxia. Furthermore, higher expression of this melatonin-responsive phase separation-network correlated with poorer overall survival in breast and gastric cancers.

This proof-of-concept synthesis positions melatonin as a remarkably versatile regulator of phase-separated oncogenic networks, capable of simultaneously modulating the integrated biophysical axes that govern cellular phase behavior. We propose that melatonin utilizes a tri-lever framework—comprising redox switching, structural intercalation, and dielectric tuning—to recalibrate the cellular solvation and fluidity landscape. By enforcing fundamental physicochemical constraints rather than targeting discrete signaling nodes, melatonin destabilizes the biophysical sanctuaries that shield oncogenic programs. This landscape-level regulation offers a strategic platform for disrupting condensate-driven malignancy, providing a biophysical logic that circumvents the diverse evasion mechanisms of the malignant cell. Competing Interest Statement The authors have declared no competing interest. Glossary/Nomenclature/Abbreviations - Abbreviation - Full Term - ADCs - Antibody-Drug Conjugates - BCs - Biomolecular Condensates - CAT - Catalase - EMT - Epithelial–Mesenchymal Transition - GO - Gene Ontology - GSH - Glutathione - ICIs - Immune Checkpoint Inhibitors - IDRs - Intrinsically Disordered Regions - LSD1 - Lysine-specific Demethylase 1A (KDM1A) - NEMO - NF-kappa-B Essential Modulator (IKBKG) - PPI - Protein-Protein Interaction - PRISMA 2020 - Preferred Reporting Items for Systematic Reviews and Meta-Analyses - PSepDB - Phase Separation Database - TAZ - Transcriptional Coactivator with PDZ-binding Motif (WWTR1) - TF - Transcription Factor - TME - Tumor Microenvironment