PPID (peptidylprolyl isomerase D), also known as cyclophilin 40 or Cyp40, is a stress-induced cytosolic chaperone that functions as a peptidyl-prolyl cis-trans isomerase involved in protein folding and mitochondrial regulation 1. Structurally, PPID possesses tetratricopeptide repeats that confer specificity for substrate binding, particularly the mitochondrial import receptor TOM70 2. The primary mechanism involves PPID-mediated insertion of outer mitochondrial membrane (OMM) proteins and regulation of mitochondrial calcium homeostasis through cyclophilin D (CypD) activity at the mitochondrial permeability transition pore (mPTP) 3. PPID plays a critical role in transient mPTP opening events essential for calcium efflux in stressed cells 3. Disease relevance is substantial. PPID dysfunction contributes to acute pancreatitis through mitochondrial calcium overload and impaired autophagy 4. In inflammatory bowel disease, PPID variants regulate macrophage mitochondrial membrane potential 5. Recently, PPID was identified as a tier 1 therapeutic target for acne, rosacea, and urticaria in proteome-wide association studies 6. Additionally, PPID inhibition has senolytics potential, promoting selective death of senescent cells through mitochondrial calcium accumulation 3. Clinically, PPID represents a promising intervention target for metabolic diseases affecting thermogenesis and body weight regulation 2, as well as age-related diseases characterized by senescent cell accumulation.