m6Am Methyltransferase PCIF1 Promotes LPP3 Mediated Phosphatidic Acid Metabolism and Renal Cell Carcinoma Progression

Abstract N6‐methyl‐2′‐O‐methyladenosine (m6Am), occurring adjacent to the 7‐methylguanosine (m7G) cap structure and catalyzed by the newly identified writer PCIF1 (phosphorylated CTD interacting factor 1), has been implicated in the pathogenesis of various diseases. However, its involvement in renal cell carcinoma (RCC) remains unexplored. Here, significant upregulation of PCIF1 and m6Am levels in RCC tissues are identified, unveiling their oncogenic roles both in vitro and in vivo. Mechanically, employing m6Am‐Exo‐Seq, LPP3 (phospholipid phosphatase 3) mRNA is identified as a key downstream target whose translation is enhanced by m6Am modification. Furthermore, LPP3 is revealed as a key regulator of phosphatidic acid metabolism, critical for preventing its accumulation in mitochondria and facilitating mitochondrial fission. Consequently, Inhibition of the PCIF1/LPP3 axis significantly altered mitochondrial morphology and reduced RCC tumor progression. In addition, depletion of PCIF1 sensitizes RCC to sunitinib treatment. This study highlights the intricate interplay between m6Am modification, phosphatidic acid metabolism, and mitochondrial dynamics, offering a promising therapeutic avenue for RCC.