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However, damaged proteins impair mitochondrial function, further contributing to several human diseases. Evidence shows mitochondrial proteases are critically important for protein maintenance. Most importantly, quality control enzymes exert a crucial role in the modulation of mitochondrial functions by degrading misfolded, aged, or superfluous proteins. Interestingly, cancer cells thrive under stress conditions that damage proteins, so targeting mitochondrial quality control proteases serves as a novel regulator for cancer cells. Not only that, mitochondrial quality control proteases have been shown to affect mitochondrial dynamics by regulating the morphology of optic atrophy 1 (OPA1), which is closely related to the occurrence and progression of cancer. In this review, we introduce mitochondrial quality control proteases as promising targets and related modulators in cancer therapy with a focus on caseinolytic protease P (ClpP), Lon protease (LonP1), high\u2010temperature requirement protein A2 (HrtA2), and OMA\u20101. Further, we summarize our current knowledge of the advances in clinical trials for modulators of mitochondrial quality control proteases. Overall, the content proposed above serves to suggest directions for the development of novel antitumor drugs.<\/jats:p>","DOI":"10.1002\/med.21929","type":"journal-article","created":{"date-parts":[[2022,10,8]],"date-time":"2022-10-08T09:32:12Z","timestamp":1665221532000},"page":"399-436","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Mitochondrial quality control proteases and their modulation for cancer therapy"],"prefix":"10.1002","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8836-4105","authenticated-orcid":false,"given":"Jiangnan","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School Sichuan University Chengdu Sichuan 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