PNKD Mediates Lactate‐Driven Tumor Progression in Clear Cell Renal Cell Carcinoma

Clear cell renal cell carcinoma (ccRCC) is a metabolically reprogrammed malignancy in which lactate accumulation is increasingly recognized as a functional driver of tumor progression rather than a passive by‐product of glycolysis. In this study, we used multiomics data and experiments to reveal lactate‐related gene expression differences and identified PNKD as a new metabolic regulator that links lactate production to cancer‐promoting signaling. Lactate‐related clustering revealed two molecular subtypes with distinct prognostic patterns, immune phenotypes, and tumor mutation burden. A five‐gene prognostic signature was established and validated, enabling robust risk stratification across cohorts. Among the signature genes, PNKD exhibited the strongest tumor‐associated expression trend and was functionally confirmed to enhance lactate production, accelerate cell‐cycle progression, and promote tumor growth. Mechanistically, PNKD activated the PI3K–AKT–mTOR axis, and pharmacological PI3K inhibition reversed PNKD‐induced metabolic and proliferative phenotypes in vitro and in vivo. Moreover, spatial colocalization of PNKD and phosphorylated ribosomal protein S6 (p‐S6) in xenografts indicated that PNKD‐high regions represent metabolically active proliferative niches. These findings establish PNKD as a lactate‐driven oncogenic effector and highlight the therapeutic potential of targeting lactate metabolism–signaling crosstalk in ccRCC.