CD276 promotes lipid metabolic reprogramming and regulates ferroptosis in clear cell renal cell carcinoma by upregulating FASN expression via SREBP1.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma, characterized by dysregulated lipid metabolism and therapy resistance, leading to a poorer prognosis than other subtypes. This study investigates the role of the immune checkpoint molecule CD276 in lipid metabolic reprogramming and the regulation of ferroptosis in ccRCC. Clinical sample analysis, in vitro experiments, and animal models revealed that CD276 is significantly overexpressed in ccRCC and positively correlated with an unfavorable prognosis. Mechanistically, CD276 activates the transcription factor sterol regulatory element-binding protein 1 (SREBP1), upregulates the expression of fatty acid synthase (FASN), promotes de novo fatty acid synthesis, and drives lipid accumulation. Concurrently, CD276-mediated lipid metabolic reprogramming suppresses ferroptosis in ccRCC cells by increasing reduced glutathione levels and enhancing glutathione peroxidase 4 activity. In vivo experiments confirmed that inhibiting CD276 significantly suppresses tumor growth and enhances the efficacy of ferroptosis inducers. This study reveals the pivotal role of the CD276-SREBP1-FASN axis in regulating lipid metabolism and ferroptosis in ccRCC, providing a theoretical basis for CD276-targeted therapy combined with ferroptosis induction as a treatment strategy for ccRCC.