Abstract

The lysosomal regulator complex member LAMTOR1 serves as a crucial pivot that recruits the mechanistic target of rapamycin complex 1 (mTORC1) to the lysosomal surface, thereby influencing biological processes such as cell growth and cancer progression. In renal cell carcinoma (RCC), existing studies reveal that mTORC1 signaling contributes to cancer progression. However, the precise regulatory mechanisms underlying mTOR signaling in RCC remain unclear and warrant further investigation. Here, we demonstrate that the palmitoylation enzyme Zinc Finger DHHC-Type Containing 9 (ZDHHC9) activates the mTOR signaling pathway, thereby accelerating cancer progression and highlighting its potential role in RCC. In our study, we identified that ZDHHC9 specifically palmitoylates LAMTOR1 at its Cys3/4 residues, enhancing the recruitment of mTORC1 and subsequently activating the mTOR signaling cascade. Collectively, our findings provide novel insights into the pathogenesis of RCC and establish ZDHHC9 as a key mediator of RCC progression through the palmitoylation of LAMTOR1, which may serve as a promising target for the diagnosis and treatment of this malignancy.