Therapeutic targeting SPI1 in combination with erastin promotes ferroptosis in ccRCC

Abstract Clear cell renal cell carcinoma is the most common renal cell carcinoma subtype with a poor prognosis. The SPI1/Pu.1, which encodes a member of the E26-transformation-specific family of transcription factors, is highly expressed and associated with poor prognosis in renal cell carcinoma. Ferroptosis, a form of cell death distinct from apoptosis, pyroptosis, and necrosis, is characterized by iron accumulation and lipid peroxidation. Although the role of SPI1 in renal cell carcinoma is recognized, its relationship with ferroptosis remains unclear. In this study, we demonstrate that SPI1 is differentially overexpressed in renal cell carcinoma and associated with unfavorable prognosis. We also show that knockdown of SPI1 enhances erastin-induced ferroptosis. Furthermore, combining EZH2 inhibitors with erastin similarly promotes ferroptosis in renal cancer cells. Mechanistically, SPI1 transcriptionally suppresses ACSL4 expression through the EZH2/H3K27me3 pathway, leading to inhibition of intracellular lipid peroxidation. Thus, SPI1 knockdown synergizes with erastin to promote lipid peroxidation and ferroptosis, suggesting that targeting SPI1 may represent a promising therapeutic strategy for renal cell carcinoma.