Mitochondrial Protease ClpP: Cancer Marker and Drug Target

Background: The human mitochondrial ClpP is a serine protease located in the mitochondrial matrix responsible for degrading short lived regulatory proteins as well as misfolded or damaged proteins, thereby maintaining cellular homeostasis. Proteastasis dysregulation is linked to tumor progression. Methods: We conducted a literature review (2020–2025) using PubMed and Scopus, focusing on studies addressing ClpP structure, function, activity modulation, and cancer relevance. Keywords included “ClpP”, “ClpP activators”, “ClpP inhibitors”, and “mitochondrial protease”. Results: ClpP is upregulated in many tumors compared to normal tissues. Cancer cells depend on ClpP for mitochondrial proteostasis, metabolic adaptation, and survival. ClpP proteolytic activity modulation—via activators or inhibitors—disrupts these processes showing efficacy even in clinical setting. Conclusions: ClpP is emerging as a key player in cancer pathophysiology and holds potential as a therapeutic target. Its selective overexpression in tumors, along with its involvement in mitochondrial homeostasis, makes it a compelling candidate for precision oncology.