biostudies-literatureLi HQian De Young Talent Nurturing ProjectChina Postdoctoral Science FoundationNational Natural Science Foundation of ChinaScience-Health Joint Medical Scientific Research Project of ChongqingGeneral Project of Chongqing Natural Science FoundationGraduate Tutor Team Construction Project of Chongqing Medical UniversityChongqing Postdoctoral Science Foundatione09769https://www.ebi.ac.uk/biostudies/studies/S-EPMC12713097biostudies-literatureUnknown12(47)The molecular mechanisms of estrogen receptor α (ERα)-positive breast carcinogenesis and endocrine resistance remain unclear. This study identifies ADP-ribosylation factor-like protein 3 (ARL3) as a key oncogenic regulator overexpressed in ERα-positive breast cancer cells and tissues. Mechanistically, ARL3 stabilizes ERα as a novel chaperone via direct binding, enhancing ESR1-driven transcription and cell proliferation. Genetic ablation of ARL3 induces ERα ubiquitination-dependent degradation, activating mTOR/AMPK pathways and causing mitophagy/mitochondrial dysfunction. ARL3 maintains ERα stability by upregulating USP10, which removes K48/K63-linked polyubiquitin chains from ERα at the K252 site. In preclinical models, the small-molecule inhibitor A-1331852 (targeting ARL3) potently supprAdvanced science (Weinheim, Baden-Wurttemberg, Germany)ARL3 Enhances ERα Stability via USP10 Deubiquitination to Promote Endocrine Resistance and Drive Mitochondrial Metabolic Reprogramming in HR+ Breast Cancer.PMC1271309782403086cqmudstd202212CSTB2023NSCQ-BHX00232025QDPY-022023MD734130CSTB2025NSCQ-GPX11512025DBXM005Shen MLi HPeng YLan AShu DHe KGuo SLiu SLi KYu HLiu XLiu YJin ACai ZGao SfalseARL3 Enhances ERα Stability via USP10 Deubiquitination to Promote Endocrine Resistance and Drive Mitochondrial Metabolic Reprogramming in HR+ Breast Cancer.The molecular mechanisms of estrogen receptor α (ERα)-positive breast carcinogenesis and endocrine resistance remain unclear. This study identifies ADP-ribosylation factor-like protein 3 (ARL3) as a key oncogenic regulator overexpressed in ERα-positive breast cancer cells and tissues. Mechanistically, ARL3 stabilizes ERα as a novel chaperone via direct binding, enhancing ESR1-driven transcription and cell proliferation. Genetic ablation of ARL3 induces ERα ubiquitination-dependent degradation, activating mTOR/AMPK pathways and causing mitophagy/mitochondrial dysfunction. ARL3 maintains ERα stability by upregulating USP10, which removes K48/K63-linked polyubiquitin chains from ERα at the K252 site. In preclinical models, the small-molecule inhibitor A-1331852 (targeting ARL3) potently suppr2025-01-01T00:00:00Z2025 Dec2026-06-06T04:31:16.371Z2026-05-25T03:11:43.041ZS-EPMC127130974104747710.1002/advs.202509769