HSPE1 (heat shock protein family E member 1) is a mitochondrial co-chaperonin that functions primarily in protein quality control and mitochondrial dynamics. As a co-chaperonin partner with HSPD1 (Hsp60), HSPE1 facilitates the proper folding of imported mitochondrial proteins and prevents misfolding under stress conditions 1. The functional mechanism involves formation of heptameric ring complexes with Hsp60 that sequester unfolded substrate proteins in a protected cavity, allowing ATP-dependent refolding cycles [UniProt annotation]. Critically, HSPE1 exhibits disease-specific roles beyond canonical chaperone function. In cancer progression, HSPE1 is upregulated and promotes tumor development through multiple mechanisms: in osteosarcoma, HSPE1 knockdown reduced cell proliferation, migration, and tumorigenicity 2; in lung adenocarcinoma, HSPE1 enhanced aerobic glycolysis to promote progression 3; in bladder cancer, HSPE1 inhibited ferroptosis via glutathione-dependent suppression of GPX4 4. Conversely, in heart failure, HSPE1 is downregulated as part of broader mitochondrial quality control dysfunction 5. Notably, HSPE1 independently controls mitochondrial morphology through OPA1 processing via stress-activated OMA1 proteolysis, distinct from its chaperonin activities 1. In Down syndrome and Kawasaki disease, dysregulated HSPE1 expression correlates with pathological development 67. HSPE1 represents a promising therapeutic target across multiple malignancies and mitochondrial diseases.