Histone H3K18 Lactylation Promotes the Malignant Progression of Wilms Tumor via a PSRC1/AKT/HIF‐1α Positive Feedback Loop

ABSTRACT Nephroblastoma, also known as Wilms tumor (WT), is the most common pediatric renal malignancy. Current treatment regimens exhibit limited efficacy in high‐risk patients and are associated with long‐term adverse effects. Through gene set enrichment analysis (GSEA) and validation using clinical specimens, we identified aberrant glycolytic activity in WT, which drives lactate accumulation. Lactate is not merely a metabolic byproduct but also a critical epigenetic regulator that mediates histone lactylation; however, its functional role in WT remains uncharacterized. In this study, we found that the hyperlactate microenvironment induced by abnormal glycolysis in WT significantly upregulates the level of histone H3K18 lactylation (H3K18la). Functional experiments confirmed that histone lactylation promotes WT cell proliferation and migration. Mechanistically, H3K18la, catalyzed by its “writer” p300, directly marks the promoter region of the downstream target gene PSRC1 and transcriptionally activates its expression. PSRC1 then acts as a key “molecular competitor,” binding to AKT in a competitive manner with the phosphatase PTEN. This interaction relieves PTEN‐mediated dephosphorylation inhibition of AKT, thereby activating the AKT/mTOR signaling pathway and enhancing the protein stability of its downstream effector HIF‐1α. Concurrently, HIF‐1α functions as a transcription factor to directly bind to the PSRC1 promoter, synergizing with H3K18la to further amplify PSRC1 transcription. In summary, this study identifies a positive feedback loop: “H3K18la→PSRC1→AKT/mTOR→HIF‐1α→PSRC1.” This mechanism dynamically links tumor metabolic abnormalities, histone modifications, and key oncogenic signaling pathways, which collectively drive the malignant progression of WT. These findings provide a novel theoretical basis for the stratified diagnosis and targeted therapy of WT.