ARL3 Enhances ERα Stability via USP10 Deubiquitination to Promote Endocrine Resistance and Drive Mitochondrial Metabolic Reprogramming in HR+ Breast Cancer.

ABSTRACT: 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 suppr

SUBMITTER: Li H 

PROVIDER: S-EPMC12713097 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature