NAT10 inhibits ferroptosis and promotes the progression of renal clear cell carcinoma by regulating the NFE2L1-GPX4 signaling pathway.

[OBJECTIVE] Clear cell renal cell carcinoma (ccRCC) is a prevalent pathological subtype of renal cell carcinoma that arises from renal tubular epithelial cells. ccRCC has long been characterized by high mortality, and at present, surgical resection is the only curative treatment, but its effectiveness is low and survival rates are low. N-acetyltransferase 10 (NAT10) is a protein that acts as an acetyltransferase, has distinct catalytic and regulatory functions, and is involved in the progression of various cancers such as bladder cancer, hepatocellular carcinoma, and multiple myeloma. Ferroptosis is a novel form of programmed cell death that is iron-dependent and distinct from apoptosis, necrosis, and autophagy. Therefore, this study aimed to investigate the potential functions of NAT10 in this context, with a particular focus on its interactions and mechanisms involving ferroptosis.

[METHODS] In this study, immunohistochemistry, immunofluorescence, and Western blotting were utilized to evaluate the changes of NAT10 and ferroptosis-related marker proteins. Plasmid vectors were utilized to establish stable ccRCC cell lines with NAT10 overexpression and knockdown. Cell proliferation, scratch, and invasion assays were conducted to assess the impact of NAT10 modification on cell proliferation and migration capabilities. Meanwhile, remodelin hydrobromide (HBr) treatment was given to ccRCC cells to observe the variations in cell proliferation ability and ferroptosis marker proteins.

[RESULTS] Our study demonstrated that NAT10 can enhance the malignant biological behavior of ccRCC, while simultaneously inhibiting markers associated with ferroptosis.

[CONCLUSIONS] Therefore, this study suggests that NAT10 may exert a pro-cancer effect by modulating the nuclear factor erythroid-2, like-1(NFE2L1)-glutathione peroxidase-4(GPX4)signaling pathway in ccRCC, indicating its potential as a new therapeutic target for this malignancy.