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FIGURE 1 2.1 Epigenetic regulation and chromatin remodeling Epigenetic alterations constitute a critical factor driving both the induction and maintenance of the reversible DTP phenotype ( 2.2 Transcriptional plasticity and gene regulatory networks Reversible DTP formation is closely associated with transcriptional rewiring, enabling cells to adapt to therapeutic stress temporarily ( 0 /G 1 arrest and metabolic rewiring that supports survival under cytotoxic stress ( 2.3 Metabolic reprogramming as an adaptive response Reversible metabolic adaptations critically support the persistence phenotype ( + cell populations ( Elevated OXPHOS activity not only supports reduced proliferation rates but also limits reactive oxygen species (ROS) accumulation, thereby protecting DTP cells from oxidative stress-induced death ( 2.4 Influence of the tumor microenvironment (TME) The reversibility of the DTP state is also regulated by dynamic interactions with the tumor microenvironment

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