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The limit therapeutic progress has been made in MM patients with cancer relapse, necessitating deeper research into the molecular mechanisms underlying its occurrence and development. A genome\u2010wide CRISPR\u2010Cas9 loss\u2010of\u2010function screening was utilized to identify potential therapeutic targets in our research. We revealed that COQ2 plays a crucial role in regulating MM cell proliferation and lipid peroxidation (LPO). Knockout of COQ2 inhibited cell proliferation, induced cell cycle arrest and reduced tumour growth in\u00a0vivo. Mechanistically, COQ2 promoted the activation of the MEK\/ERK cascade, which in turn stabilized and activated MYC protein. Moreover, we found that COQ2\u2010deficient MM cells increased sensitivity to the LPO activator, RSL3. Using an inhibitor targeting COQ2 by 4\u2010CBA enhanced the sensitivity to RSL3 in primary CD138<jats:sup>+<\/jats:sup> myeloma cells and in a xenograft mouse model. 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Together, our findings suggest that COQ2 promotes cell proliferation and tumour growth through the activation of the MEK\/ERK\/MYC axis and targeting COQ2 could enhance the sensitivity to ferroptosis in MM cells, which may be a promising therapeutic strategy for the treatment of MM patients.<\/jats:p>","DOI":"10.1111\/bjh.19375","type":"journal-article","created":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T05:55:00Z","timestamp":1710136500000},"page":"1307-1324","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification of COQ2 as a regulator of proliferation and lipid peroxidation through genome\u2010scale CRISPR\u2010Cas9 screening in myeloma cells"],"prefix":"10.1111","volume":"204","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7227-3460","authenticated-orcid":false,"given":"Miao","family":"Li","sequence":"first","affiliation":[{"name":"Department of Dermatovenereology, Pelvic Floor Disorders 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