CLPP encodes the proteolytic subunit of the mitochondrial ClpXP complex, a serine-type endopeptidase essential for ATP-dependent protein degradation in the mitochondrial matrix 1. As a core component of mitochondrial protein quality control, ClpP degrades misfolded proteins and cleaves specific substrates including PINK1 2. The ClpXP complex exhibits broad housekeeping functions rather than substrate-specific degradation, maintaining mitochondrial proteostasis through selective protein removal 3. Clinically, CLPP hyperactivation represents a therapeutic vulnerability in cancer. Imipridone activators of ClpP selectively kill cancer cells by inducing excessive proteolysis of respiratory chain proteins, disrupting mitochondrial function while sparing non-malignant cells 1. This strategy shows efficacy across multiple cancer types: diffuse midline gliomas respond to imipridone-mediated ClpP activation through metabolic impairment and cell differentiation 4, while acute myeloid leukemia cells resistant to standard therapies show sensitivity to ClpP agonists combined with other mitochondrial inhibitors 5. ClpP activation also enhances ferroptosis in AML by degrading electron transport chain components 6. Conversely, CLPP loss-of-function causes Perrault syndrome, characterized by hearing loss and ovarian insufficiency, reflecting ClpP's role in mitochondrial homeostasis during oogenesis and cellular differentiation 7.