The E3 Ubiquitin Ligase ARIH1 Facilitates Colorectal Cancer Progression by Promoting Oxidative Phosphorylation via the Mitochondrial Translocation of K63‐Linked Ubiquitinated PHB1

Abstract The RBR E3 ubiquitin ligase ARIH1 has been proven to induce specific ubiquitylation of substrates, thereby regulating cell proliferation and the cell cycle. However, the understanding of how ARIH1 influence cancer development is limited. This study revealed that ARIH1 is upregulated in colorectal cancer (CRC) cells and facilitates cell growth and metastasis. Clinically, high ARIH1 levels are linked to an unfavorable CRC prognosis. Mechanistically, ARIH1 directly interacts with PHB1 via its RING1+RBR+RING2 domains, catalyzing the K63‐linked ubiquitination of PHB1 at lysine 186 (K186). The increased interaction between PHB1 and Akt through this modification results in PHB1 phosphorylation by Akt and its subsequent translocation into mitochondria, where it maintains mitochondrial stability and promotes oxidative phosphorylation (OXPHOS). Collectively, these findings demonstrate the role of ARIH1‐mediated K63‐linked ubiquitination of PHB1 in mitochondrial dynamics and OXPHOS, suggesting that it has potential as diagnostic biomarker and treatment target for CRC.