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This study identified significant metabolic differences between metastatic and non\u2010metastatic OS samples through bioinformatics analysis, highlighting key processes such as cell proliferation, mitochondrial assembly, and changes in mitochondrial membrane permeability. Among differentially expressed genes, Pleckstrin Homology And FYVE Domain Containing 1 (PLEKHF1) was the most significantly downregulated in metastatic OS samples. Functional experiments demonstrated that PLEKHF1 overexpression in Saos\u20102 and U2OS cells induced mitochondrial dysfunction, evidenced by increased mtROS levels, decreased mitochondrial membrane potential, and altered cytochrome C distribution. Additionally, PLEKHF1 overexpression inhibited OS cell viability, colony formation, migration, invasion, and epithelial\u2010mesenchymal transition (EMT), while promoting apoptosis. Conversely, knockdown of PLEKHF1 had the opposite effects on Saos\u20102 and U2OS cells. In\u00a0vivo, PLEKHF1 overexpression reduced tumor growth and lung metastasis in a mouse model. Conversely, PLEKHF1 knockdown ameliorated Rotenone\u2010induced mitochondrial dysfunction and mitophagy, partially reversing the suppressive effects of Rotenone on OS cell aggressiveness. These findings suggest that PLEKHF1 could serve as an anti\u2010tumor factor by inducing mitochondrial dysfunction, thereby inhibiting OS growth and metastasis. The study highlights the potential of PLEKHF1 as a therapeutic target for managing osteosarcoma, providing valuable insights into the role of mitochondrial dysfunction in OS pathogenesis.<\/jats:p>","DOI":"10.1002\/iub.70048","type":"journal-article","created":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T13:09:34Z","timestamp":1757077774000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>PLEKHF1<\/scp> Induces Mitochondrial Dysfunction to Inhibit Osteosarcoma Growth and Metastasis"],"prefix":"10.1002","volume":"77","author":[{"given":"Jun","family":"Wan","sequence":"first","affiliation":[{"name":"Department of Orthopaedics Xiangya Hospital, Central South University  Changsha Hunan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyan","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Xiangya Hospital, Central South University  Changsha Hunan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhan","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Xiangya Hospital, Central South University  Changsha Hunan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yupeng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Xiangya Hospital, Central South University  Changsha Hunan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Xiangya Hospital, Central South University  Changsha Hunan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Can","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Xiangya Hospital, Central South University  Changsha Hunan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1057-126X","authenticated-orcid":false,"given":"Feng","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics Xiangya Hospital, Central South University  Changsha Hunan China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,9,5]]},"reference":[{"key":"e_1_2_16_2_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2002.20.3.776"},{"key":"e_1_2_16_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-021-00519-8"},{"key":"e_1_2_16_4_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.59.4895"},{"key":"e_1_2_16_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2017.09.036"},{"key":"e_1_2_16_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13040683"},{"key":"e_1_2_16_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy310"},{"key":"e_1_2_16_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.24121"},{"key":"e_1_2_16_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.780264"},{"key":"e_1_2_16_10_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1984.2.3.152"},{"key":"e_1_2_16_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/00003086-199109000-00003"},{"key":"e_1_2_16_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(16)30096-1"},{"key":"e_1_2_16_13_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-24-0163"},{"key":"e_1_2_16_14_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.75.1743"},{"key":"e_1_2_16_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2020.05.014"},{"key":"e_1_2_16_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-020-0341-y"},{"key":"e_1_2_16_17_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.112.268946"},{"key":"e_1_2_16_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2020.06.019"},{"key":"e_1_2_16_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/191144a0"},{"key":"e_1_2_16_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.02.035"},{"key":"e_1_2_16_21_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-1059"},{"key":"e_1_2_16_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2015.12.001"},{"key":"e_1_2_16_23_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.8.6.519"},{"key":"e_1_2_16_24_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1160809"},{"key":"e_1_2_16_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.101140"},{"key":"e_1_2_16_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2017.01.005"},{"key":"e_1_2_16_27_1","first-page":"1","article-title":"Cancer Metabolic Reprogramming: Importance, Main Features, and Potentials for Precise Targeted Anti\u2010Cancer Therapies","volume":"11","author":"Phan L. 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