Beyond catalysis: Spatial topology of GPX4 in ferroptosis and its theranostic implications

As the primary gatekeeper of ferroptosis, glutathione peroxidase 4 (GPX4) represents a compelling therapeutic target. A recent study demonstrates that sustained GPX4 blockade via sophisticated lipidic nanoplatforms simultaneously triggers robust ferroptosis and remodels the tumor immune microenvironment; however, the underlying synergistic mechanisms remain poorly elucidated. By integrating classical GPX4 enzymatic theories with recent breakthroughs regarding its membrane-bound structural functions and its secretion as an immune-disrupting ligand, we propose a framework illustrating how GPX4 serves as a nexus between intracellular survival mechanisms and extracellular immune evasion. More importantly, we delineate a "spatial topological" landscape of GPX4 to fully harness its therapeutic potential in cancer therapy.