YBX1 orchestrates LDHA-mediated metabolic reprogramming and NF-κB activation to drive clear cell renal cell carcinoma progression

Renal cell carcinoma (RCC) is sometimes referred to as a "metabolic disease", as nearly all types of RCC are associated with the reprogramming of glucose and lipid metabolism. Y-box binding protein 1 (YBX1) plays a crucial regulatory role in the development and progression of various cancers. In the early stages of our study, we analyzed the YBX1 binding proteins in 786-O cells using IP-MS and found that YBX1 is involved in the glycolysis process of RCC. Subsequent experiments showed that YBX1 is an oncogene that is significantly upregulated in RCC. Functionally, YBX1 promotes glycolysis in RCC, and both in vitro and in vivo experiments demonstrate that YBX1 contributes to the malignant progression of RCC. The correlation between YBX1 and Lactate Dehydrogenase A (LDHA) expression was predicted by bioinformatics and further explored in clinical RCC tissues. Mechanistically, YBX1 interacts with LDHA and co-localizes in the cytoplasm. CUT&Tag and functional experiments further revealed that YBX1 regulates LDHA through transcription. Additionally, YBX1 and LDHA activate the nuclear factor kappa-B (NF-κB) signaling pathway. Silencing the LDHA gene or using an LDHA inhibitor rescued the YBX1-mediated activation of the NF-κB signaling pathway and inhibited lactic acid production and RCC cell proliferation. In conclusion, these findings provide new insights into the oncogenic role of YBX1 in glycolysis and suggest that the YBX1-LDHA-NF-κB axis may represent a promising therapeutic target of RCC.