Abstract
<jats:p>Clear cell renal cell carcinoma (ccRCC) is driven by persistent HIF-2[alpha]; transcription program initiated by VHL loss, yet molecular mediators sustaining this program are poorly defined. Using single-cell transcriptomics, we identified lysyl oxidase (LOX) as a driver of ccRCC progression, selectively enriched in a hypoxia/epithelial-mesenchymal transition (EMT) gene program associated with poor outcome. While LOX oxidizes and stabilizes HIF-2[alpha]; by antagonizing HUWE1-mediated ubiquitination and degradation, thereby sustaining HIF-2[alpha];-driven transcription in cancer cells, it also remodels extracellular matrix (ECM) and promotes angiogenesis in the tumor microenvironment (TME). Genetic or pharmacological inhibition of LOX destabilizes HIF-2[alpha];, disrupts ECM, inhibits angiogenesis, and suppresses tumor initiation, growth, and metastasis in vivo. LOX inhibition enhances anti-angiogenic therapy response and remains effective in belzutifan-resistant HIF-2[alpha]; G323E-mutant tumors. Nuclear LOX protein correlates with nuclear HIF-2[alpha]; in high-grade patient tumors. Together, LOX coordinates HIF-2[alpha]; transcription program with TME and is a therapeutic target in ccRCC.</jats:p>