Hypoxia-induced PLOD3 activates the NEDD4/GOT2 axis to exacerbate renal cell carcinoma progression.

Treating renal cell carcinoma (RCC) is clinically challenging because the characteristic hypoxic microenvironment of RCC serves as a key driver of malignant progression. High-throughput sequencing analysis across multiple models was used in this study to identify PLOD3 as a major oncogene driving RCC development. PLOD3 promoted RCC cell growth and metastatic capacity in vivo and in vitro. Mechanistically, HIF-2α and histone lactylation modification jointly upregulate PLOD3 expression levels. PLOD3 specifically binds to the C2 domain of NEDD4, hindering NEDD4 autoinhibition and triggering NEDD4 to activate E3 ubiquitin ligase function. This process affects GOT2 expression via inducing K48-linked ubiquitination, leading to GOT2 degradation via the ubiquitin-proteasome pathway. Thus, PLOD3 participates in reprogramming glutamine metabolism through influencing the stability GOT2 protein. This study establishes PLOD3 as a key oncogenic driver of RCC, with HIF-2α/PLOD3/NEDD4/GOT2 pathway potentially being a therapeutic target and providing biomarkers for treating RCC.