Transcriptional activation of ALOX5 by c-Myc drives malignant progression and M2 macrophage polarization in clear cell renal cell carcinoma.

Abstract

Clear cell renal cell carcinoma (ccRCC) is an aggressive malignancy with poor prognosis, but the molecular mechanisms linking oncogenic signaling to macrophage polarization remain unclear. In this study, we identify arachidonate 5-lipoxygenase (ALOX5) as an oncogenic factor in ccRCC. Multi-omics analyses and clinical validation show that ALOX5 is up-regulated in ccRCC tissues and its high expression is associated with advanced tumor stage and poor survival. Functional assessments reveal that silencing ALOX5 in ccRCC cells inhibits cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT) in vitro, and suppresses tumor progression in vivo. Notably, ALOX5 expression in ccRCC cells is positively correlated with the polarization of infiltrating macrophages into the M2 phenotype, and the accumulation of this portion of M2-polarized tumor-associated macrophages (TAMs) in the tumor microenvironment. ALOX5 knockdown reduces macrophage migration and M2 marker expression. Mechanistically, c-Myc directly binds to the ALOX5 promoter and activates its transcription. Restoration of ALOX5 in c-Myc-silenced cells partially rescues the malignant phenotype and M2 polarization, confirming a functional c-Myc-ALOX5 axis. Collectively, our findings suggest that the c-Myc-ALOX5 pathway promotes ccRCC progression by enhancing tumor cell aggressiveness and M2 macrophage polarization, offering a potential therapeutic target for immune microenvironment modulation in renal cancer.