PIAS1 (Protein Inhibitor of Activated STAT1) is a SUMO E3 ligase that functions as a critical regulator of protein SUMOylation and transcriptional control. Its primary role involves inhibiting STAT1 phosphorylation through enhanced SUMOylation, thereby modulating immune signaling and ferroptosis responses 1. PIAS1 restricts Epstein-Barr virus lytic replication by inhibiting transcription factors required for viral gene expression, though viral caspases can antagonize this restriction 2. In cancer contexts, PIAS1 functions as a coregulator of androgen receptor signaling in breast and prostate cancer, influencing cell survival and proliferation pathways 3. Importantly, circular RNA-derived PIAS1 variants promote hepatocellular carcinoma and melanoma progression by inhibiting ferroptosis through distinct mechanisms: HCC via the miR-455-3p/NUPR1/FTH1 axis 4, and melanoma by blocking immunogenic ferroptosis via STAT1 SUMOylation modulation 1. Therapeutically, targeting circPIAS1 combined with immunotherapy enhances treatment efficacy 1. Beyond cancer, PIAS1-mediated SUMOylation regulates ROCK2 activation in allergic asthma, promoting goblet cell metaplasia 5, and participates in DNA damage repair through the CK2/PIAS1/SPOP axis, affecting PARP inhibitor sensitivity in prostate cancer 6. PIAS1 also modulates SUMOylation-dependent mitophagy in cardiovascular disease 7.