Branched‐Chain α Keto‐Acid Dehydrogenase Kinase‐Mediated AKT Phosphorylation Promotes RCC Tumorigenesis and Drug Resistance

Abstract Advanced renal cell carcinoma (RCC) primarily relies on targeted and immune‐based therapies, yet these treatments often face limitations due to inefficacy and drug resistance. Branched‐chain α‐keto‐acid dehydrogenase kinase (BCKDK) has been implicated in promoting RCC metastasis, but its specific substrates and the mechanisms underlying its regulation of RCC progression remain poorly understood. This study uncovers a novel mechanism whereby BCKDK‐mediated AKT phosphorylation drives RCC tumorigenesis and drug resistance. Elevated BCKDK expression correlates with poor prognosis in RCC clinical samples. BCKDK deficiency inhibits RCC cell proliferation and tumorigenesis both in vitro and in vivo. Mechanistic investigations reveal that BCKDK directly binds to and regulates the phosphorylation of AKT. BCKDK‐mediated phosphorylation of AKT decreases ubiquitin‐mediated AKT protein degradation, and promotes tumorigenesis via activation of the AKT/mTOR signaling pathway. RNA sequencing identifies BCKDK's involvement in the drug metabolism network and apoptotic signaling pathways. The BCKDK/AKT/ABCB1 axis mediates doxorubicin resistance. Targeting BCKDK/AKT inhibits the growth of RCC patient‐derived organoids (PDOs), enhances doxorubicin‐induced apoptosis in RCC cells, and suppresses tumor growth in vivo. These findings identify a previously unrecognized phosphorylation substrate of BCKDK and highlight the critical role of the BCKDK/AKT signaling axis in RCC progression, offering a promising target for therapeutic intervention.