Nilotinib inhibition of clear cell renal cell carcinoma proliferation and synergistic enhancement of sunitinib efficacy.

BACKGROUND: Dysregulated cholesterol metabolism is a hallmark of clear cell renal cell carcinoma (ccRCC), but therapeutic strategies targeting this vulnerability remain limited. Sterol O-acyltransferase 1 (SOAT1), a key enzyme in cholesterol esterification, is overexpressed in ccRCC and associated with poor prognosis, positioning it as a promising therapeutic target. METHODS: A lipid metabolism compound library was functionally screened in ccRCC cell lines. SOAT1 targeting was validated via siRNA knockdown and overexpression rescue experiments. The potency of nilotinib was compared with avasimibe using CCK-8 assays. Synergistic effects with sunitinib were assessed in vitro and in a xenograft mouse model. Lipid droplet accumulation was evaluated by Nile red staining, and lipidomic profiling was conducted by LC-MS/MS. RESULTS: Avasimibe was identified as a SOAT1-targeting inhibitor that suppresses ccRCC proliferation through cholesterol metabolic remodeling. SOAT1 overexpression in ccRCC tissues correlated with poor patient prognosis. The high-affinity SOAT1 inhibitor nilotinib demonstrated superior potency to avasimibe, acting at lower concentrations. Nilotinib synergized with sunitinib to enhance anti-tumor efficacy while reducing intratumoral Ki-67 expression. Mechanistically, nilotinib disrupted SOAT1-mediated lipid droplet formation, consistent with lipidomic findings showing downregulation of cholesteryl esters. CONCLUSION: This study identifies nilotinib as a high-affinity SOAT1 inhibitor with superior potency to avasimibe. Its synergistic activity with sunitinib in suppressing ccRCC proliferation supports clinical evaluation as monotherapy or in combination.