PPIF encodes peptidylprolyl isomerase F (cyclophilin D), a mitochondrial enzyme catalyzing cis-trans isomerization of proline peptide bonds to facilitate protein folding 1. Its primary pathological role centers on regulating the mitochondrial permeability transition pore (mPTP), where it promotes transient opening events critical for calcium efflux; senescent cells exhibit heightened mPTP flickering dependent on CypD activity for survival 2. PPIF mediates mitochondrial dysfunction through calcium overload-dependent and -independent mechanisms involving ATP synthase interaction, triggering downstream ER stress, autophagy impairment, and cell death pathways 3. Disease relevance spans inflammatory conditions: in inflammatory bowel disease, PPIF regulation by enhancer variants alters macrophage mitochondrial membrane potential 4; in hypertension, CypD acetylation promotes endothelial dysfunction and oxidative stress 5; in intracranial aneurysm, CypD-mediated ROS production activates the 8-OHdG/NLRP3/MMP9 pathway driving vascular damage 6. Additionally, PPIF overexpression associates with poor prognosis in endometrial cancer and multiple myeloma 78, while neutrophil PPIF exacerbates lung ischemia-reperfusion injury via calcium overload and neutrophil extracellular trap formation 9. Clinically, PPIF inhibition using cyclosporin A shows therapeutic potential across multiple pathologies by preventing mitochondrial calcium accumulation and associated cellular dysfunction.