Systemic redox switching of transcription factors: A context-sensitive framework for cell fate decisions.

Transcription factors often exhibit a striking paradox: they function as tumor suppressors in one context and promote oncogenesis in another. The underlying mechanisms of this context dependence have remained elusive. We propose a novel conceptual framework, systemic redox switching, to resolve this paradox. Based on our research on upstream stimulatory factor 2 (USF2) and convergent observations on other factors, our model suggests that redox regulation is network-embedded rather than driven by discrete cysteine switches. We propose that transcription factors occupy distinct regulatory regimes (homeostatic, adaptive, and survival states) which are connected by threshold-like, hysteretic transitions. Beyond classical graded input-output views, this framework explicitly posits discrete, hysteretic regime transitions at the transcriptional-network level and links them to a minimal dynamical model of the USF2-TFEB-NRF2-redox motif. These transitions convert continuous redox inputs into distinct changes in promoter occupancy and transcriptional programs. USF2 exemplifies a kinase-integrated, non-canonical switch that decodes mitochondrial and autophagy signals via phosphorylation (e.g., Ser155) and context-dependent cooperation with NRF2 and HIFs. Extending this logic to diverse archetypes (NRF2, HIFs, FOXOs, c-MYC, and AHR) demonstrates the framework's generalizability. The model is experimentally tractable; targeted perturbations of primary sensing modules (e.g., KEAP1 mutation, PHD inhibition, or USF2 phosphorylation disruption) should predictably alter regime transitions. By reframing paradoxical behaviors as controlled state transitions, this framework provides a unifying, network-level understanding with direct implications for targeting therapies in cancer, metabolic diseases, and age-related pathologies.