The Role of Cyclophilin D (CypD) in Cancer

Cyclophilin D (CypD) is a central regulator of mitochondrial physiology and cell fate. Its best-established function is to sensitize the mitochondrial permeability transition pore (mPTP), a high-conductance channel of the inner mitochondrial membrane activated by matrix Ca2+ overload and oxidative stress. Sustained CypD-dependent mPTP opening contributes to bioenergetic collapse and predominantly necrotic cell death in ischemia/reperfusion injury, neurodegeneration, and metabolic disease. In cancer, however, CypD functions are highly context-dependent. Increased CypD expression or activity supports mitochondrial fitness, metabolic adaptation, proliferation, or therapy resistance in some tumor models, whereas CypD-dependent pore opening mediates the cytotoxicity of several anticancer agents in others. These divergent outcomes depend on tumor type, CypD post-translational state, and interactions with chaperones, metabolic enzymes, tumor suppressors, and oncogenic kinases. This review critically synthesizes the current evidence on CypD in mitochondrial regulation and cancer biology, emphasizing cell-death evasion, tumor progression, invasion, drug resistance, and the therapeutic implications of either inhibiting or activating CypD-dependent pathways.