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Mitofusin 2 (MFN2) is an important GTPase involved in mitochondrial fusion, energy balance and mitophagy. The role and regulatory mechanism of MFN2 in HCC progression and lenvatinib resistance remain unclear. Herein, we demonstrated that the family with sequence similarity 111 member B (FAM111B) regulated the stability of MFN2 and the sensitivity to lenvatinib in HCC. Mechanistically, FAM111B promoted MFN2 ubiquitination by recruiting RAN-binding protein 9 (RANBP9), a core subunit of the C-terminal to LisH (CTLH) E3 ligase complex. Targeting FAM111B generated hyperfused mitochondria, driving a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) and antagonising cytoprotective mitophagy. Clinically, FAM111B protein levels were inversely correlated with MFN2 expression in HCC samples, with patients who exhibited high FAM111B levels having a worse prognosis and reduced sensitivity to lenvatinib treatment. More importantly, we developed glypican-3 (GPC3)-targeted lipid nanoparticles for efficient delivery of siFAM111B, which demonstrated strong efficacy in combination with lenvatinib. Together, our findings uncover a novel regulatory mechanism for MFN2 posttranscriptional regulation and highlight the therapeutic potential of targeting FAM111B in HCC treatment.<\/jats:p>","DOI":"10.1038\/s41419-025-07941-1","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T15:49:44Z","timestamp":1756136984000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Targeting FAM111B attenuates mitophagy and increases the sensitivity to lenvatinib treatment by increasing MFN2 stability in hepatocellular carcinoma"],"prefix":"10.1038","volume":"16","author":[{"given":"Yu-Chuan","family":"Yan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Juan","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang-Xiao","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo-Qiang","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui-Zhe","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-jia","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi-Niu","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Lu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Feng","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6056-2097","authenticated-orcid":false,"given":"Zhao-Ru","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5108-1774","authenticated-orcid":false,"given":"Tao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,25]]},"reference":[{"key":"7941_CR1","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.1056\/NEJMra1713263","volume":"380","author":"A Villanueva","year":"2019","unstructured":"Villanueva A. 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Use of human data and human tissue in this study was approved by the Medical Ethics Committee of Qilu Hospital of Shandong University (KYLL-202111-015). Informed consent was obtained from all participants. The use of animals in this study was also approved by the Medical Ethics Committee of Qilu Hospital of Shandong University.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"645"}}