Candidate Adaptive Resistance Mechanisms to Dual Fuel Modulation (DFM) in Glioblastoma: A Molecular and Epitranscriptomic Perspective

However, an important unanswered question is how surviving tumor cells adapt to this stress and restore metabolic and redox homeostasis. This companion hypothesis proposes that DFM-induced metabolic stress may activate layered resistance programs involving transcriptional, chromatin, epitranscriptomic, and non-coding RNA regulation.

Four candidate adaptive axes are considered: ATF4/NRF2-associated stress responses; miRNA–lncRNA regulation potentially preserving SLC7A11/GPX4 activity; metabolically influenced chromatin remodeling involving acetyl-CoA, H3K27ac, and BRD4-associated transcription; and a DAMER–ALKBH5–ATF4 epitranscriptomic mechanism previously implicated in nutrient-stress adaptation in cancer models. These mechanisms are not assumed to operate universally or simultaneously.