SENP3 is a SUMO-specific protease that catalyzes the deconjugation of SUMO2 and SUMO3 from target proteins, with only weak activity against SUMO1 conjugates. The enzyme regulates diverse cellular processes through desumoylation of substrates including MEF2D, which enhances transcriptional activation, and nucleophosmin (NPM1), required for ribosomal RNA processing. SENP3 functions as a redox sensor that can enhance HIF1A transcriptional activity by desumoylating EP300, and participates in the Five Friends of Methylated CHTOP (5FMC) complex to modulate ZNF148 transactivation. Disease relevance spans multiple cancer types and non-neoplastic conditions. In hepatocellular carcinoma, the METTL16-SENP3-lactotransferrin axis confers ferroptosis resistance and promotes tumor progression 1. SENP3 loss in macrophages promotes M2 polarization and accelerates breast cancer malignancy through enhanced Akt1 SUMOylation 2, while SENP3 mediates deSUMOylation of SIX1 to drive prostate cancer proliferation and migration 3. Recent studies demonstrate SENP3 sensitizes macrophages to ferroptosis via deSUMOylation of FSP1 4, and regulates neuronal ferroptosis after spinal cord injury by antagonizing TRIM28-mediated ACSL4 SUMOylation 5. Clinically, high SENP3 expression predicts poor prognosis in hepatocellular carcinoma, and targeting the METTL16-SENP3-lactotransferrin axis represents a strategy to sensitize ferroptosis in HCC 1. The TRIM28-ACSL4 regulatory axis with SENP3 involvement offers potential therapeutic opportunities; ferroptosis inhibitor liproxstatin-1 and the FDA-approved compound rutin hydrate show promise in preclinical models.