Manoalide targets redox-mitochondrial vulnerability to induce bioenergetic failure and suppress angiogenic activity in glioblastoma.

Glioblastoma (GBM) displays pronounced metabolic adaptability and resistance to cell death, largely sustained by mitochondrial redox homeostasis. Targeting redox imbalance has emerged as a promising strategy; however, the relationship between phospholipase A2 (PLA2)-related signaling, mitochondrial dysfunction, and bioenergetic failure in GBM remains insufficiently defined. Bioinformatic analyses using TCGA and GTEx datasets revealed that phospholipase A2 group IVA (PLA2G4A) was upregulated in glioma and associated with unfavorable overall survival. PLA2G4A expression also showed modest but statistically significant correlations with selected redox and mitochondrial function-related genes, suggesting a possible association between PLA2-related signaling and the redox-mitochondrial state of glioma. Accordingly, we investigated whether manoalide, a marine-derived sesterterpenoid previously reported to inhibit PLA2 activity, could perturb mitochondrial redox equilibrium and promote oxidative stress-associated cytotoxicity in GBM cells. Manoalide induced intracellular and mitochondrial oxidant-associated fluorescence signals, accompanied by reduced antioxidant defenses and loss of mitochondrial membrane potential. Bioenergetic profiling revealed impaired oxidative phosphorylation, reduced oxygen consumption, and ATP depletion, indicating mitochondrial dysfunction. Antioxidant pretreatment with N-acetylcysteine attenuated oxidant-associated fluorescence signals, preserved mitochondrial membrane potential, and reduced apoptosis-associated signaling, suggesting that manoalide cytotoxicity is mediated at least in part through redox-associated mechanisms. Sustained oxidative stress was accompanied by autophagy-associated responses characterized by acidic vesicular organelle formation, LC3-II accumulation, and p62 elevation. These effects may be linked to the electrophilic α,β-unsaturated γ-lactone moiety of manoalide, which may contribute to its redox-modulating properties. In addition to tumor cell-intrinsic effects, manoalide suppressed endothelial migration, tube formation, and microvessel sprouting, suggesting anti-angiogenic activity in complementary endothelial and ex vivo angiogenesis models. Collectively, our findings integrate PLA2G4A-based transcriptomic evidence with functional analyses, suggesting manoalide-mediated disruption of mitochondrial redox homeostasis may represent a potential strategy to induce bioenergetic dysfunction, apoptosis-associated signaling, autophagy-associated stress responses, and anti-angiogenic activity in glioblastoma.