This study aims to investigate the role and mechanism of ubiquitin-specific protease 3 (USP3) in cisplatin (DDP) in non-small cell lung cancer (NSCLC). USP3 expression in NSCLC cells was detected using reverse transcription quantitative PCR and Western blot. DDP-resistant cells were constructed and cell counting kit-8 assay determined the IC 50 of cells to DDP. USP3 expression was silenced in DDP-resistant cells, followed by detection of cell proliferation by clone formation assay, iron ion contents, ROS, MDA, and GSH levels by kits, GPX4 and ACSL4 protein expressions by Western blot. The binding between USP3 and ACOT7 was analyzed using Co-IP, and the ubiquitination level of ACOT7 was measured. USP3 and ACOT7 were highly expressed in NSCLC cells and further increased in drug-resistant cells. USP3 silencing reduced the IC 50 of cells to DDP and diminished the number of cell clones. Moreover, USP3 silencing suppressed GSH and GPX4 levels, upregulated iron ion contents, ROS, MDA, and ACSL4 levels, and facilitated ferroptosis. Mechanistically, USP3 upregulated ACOT7 protein expression through deubiquitination. ACOT7 overexpression alleviated the promoting effect of USP7 silencing on ferroptosis in NSCLC cells and enhanced DDP resistance. To conclude, USP3 upregulated ACOT7 protein expression through deubiquitination, thereby repressing ferroptosis in NSCLC cells and enhancing DDP resistance.
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