Dual Fuel Modulation (DFM): A Precision Metabolic Platform for Exploiting Ferroptotic Vulnerability and Metabolic Plasticity in Glioblastoma

Dual Fuel Modulation (DFM) is proposed as a hypothesis-generating metabolic framework designed to investigate whether this adaptive capacity can be converted into a therapeutic vulnerability through coordinated perturbation of interconnected metabolic systems.</p><p dir="ltr"><br></p><p dir="ltr">Rather than assuming that GBM is uniformly dependent on a single metabolic pathway, DFM proposes that selected tumor phenotypes may become vulnerable when glycolytic flux, cystine-dependent antioxidant capacity, membrane lipid susceptibility to peroxidation, and compensatory mitochondrial metabolism are challenged within an experimentally defined therapeutic window.

The framework integrates four conceptual pressures: controlled glycolytic modulation; impairment of System Xc⁻-dependent cystine utilization and glutathione homeostasis; enhancement of lipid-peroxidation susceptibility through selected polyunsaturated fatty acids (PUFAs); and partial modulation of mitochondrial oxidative phosphorylation to reduce metabolic compensation.</p><p><br></p><p dir="ltr">DFM remains a testable systems-level hypothesis rather than a validated therapeutic regimen.