Manganese (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) represses sulfide:quinone oxidoreductase expression and targets the sulfido-redox system in glioblastoma models

The adaptation of the redox system and bioenergetics is a major factor contributing to cancer metabolism. Redox therapy is promising but still requires molecular studies that consider the reactive species interactome (RSI) concept, which integrates reactive oxygen, nitrogen, sulfur, carbonyl species, and redox enzymes. Our aim was to decipher the role of the RSI in glioblastoma (GBM), including by challenging the RSI with the MnTBAP redox agent. The effects of MnTBAP on the redox system and bioenergetics were investigated on several GBM models, namely <i>in vitro</i> 2D culture, <i>in vitro</i> 3D culture with two human GBM tumoroids, and <i>in vivo</i> preclinical model, which included male and female comparisons. We show – for the first time – that MnTBAP represses the sulfide:quinone oxidoreductase (SQOR) involved in the sulfur metabolism and bioenergetics, and targets the RSI through the sulfido-redox system. Through <i>in vitro</i> silencing and overexpression approaches, we also demonstrate that SQOR contributed to GBM cell growth and that its decrease is involved in the molecular effect of MnTBAP. Consequently, MnTBAP induces a switch between apoptosis, uncontrolled necrosis, and ferroptosis depending on the glioblastoma models. Our findings represent the next step in establishing a better understanding of redox biology in the context of GBM.