Abstract

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.