Herein, we demonstrate that ARL3 promotes breast cancer progression and tamoxifen resistance through coordinating dual regulatory mechanisms, stabilizing ERα through USP10‐mediated deubiquitination of both K48‐ and K63‐linked chains and modulating ERα‐mTOR/AMPK crosstalk to enhance mitochondrial oxidative phosphorylation (OXPHOS). The gene discussed is ESR1; the disease is breast cancer.