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Given the pivotal role of mitochondrial reprogramming in tumor progression, we investigated the contribution of mitochondrial ribosomal protein L3 (MRPL3) to postoperative early recurrence and its underlying mechanisms. Label-free quantitative proteomic profiling of HCC tissues identified MRPL3 as a recurrence-associated candidate. Its overexpression in HCC was confirmed by qRT-PCR, western blotting, and immunohistochemistry, and correlated with poor disease-free and overall survival. Functional assays demonstrated that MRPL3 enhances HCC cell proliferation, migration, and invasion both in vitro and in vivo by improving mitochondrial respiration, membrane potential, and ATP production while reducing reactive oxygen species levels. Mechanistically, MRPL3 associates with TOMM40, a core component of the mitochondrial outer membrane translocase complex, through its \u0394R1 (1\u2013174 aa) region and the \u0394R2 (181\u2013361 aa) domain of TOMM40, forming a protein complex that contributes to the activation of the PGC-1\u03b1\/TFAM signaling pathway. Disruption of this axis abrogated the metabolic and oncogenic effects of MRPL3. Collectively, these findings identify MRPL3 as a key mitochondrial regulator that promotes metabolic reprogramming and drives early recurrence of HCC through the TOMM40\/PGC-1\u03b1\/TFAM axis, suggesting its potential as a prognostic biomarker and therapeutic target to prevent postoperative relapse.<\/jats:p>","DOI":"10.1038\/s41419-026-08968-8","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T05:15:25Z","timestamp":1780982125000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MRPL3 enhances mitochondrial function via the TOMM40\/PGC-1\u03b1\/TFAM axis to drive early recurrence in hepatocellular carcinoma"],"prefix":"10.1038","volume":"17","author":[{"given":"Shubin","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wuhan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teng","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiyan","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaokuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huifang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Nie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3100-4517","authenticated-orcid":false,"given":"Zhiyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"8968_CR1","first-page":"498","volume":"75","author":"D Moris","year":"2025","unstructured":"Moris D, Martinino A, Schiltz S, Allen PJ, Barbas A, Sudan D, et al. 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