PIAS3 (protein inhibitor of activated STAT3) functions as an E3 SUMO ligase that negatively regulates STAT3 signaling and multiple transcriptional pathways. Located on chromosome 1 1, PIAS3 inhibits STAT3 DNA-binding activity and suppresses cell growth 2. Beyond STAT3 regulation, PIAS3 modulates transcription through diverse mechanisms: it antagonizes ATF1-mediated repression of the ferritin H gene by blocking ATF1 DNA-binding 3, and mediates SUMOylation of substrates including RNF146 and CCAR2 to regulate signaling pathways 4. Reduced PIAS3 expression associates with multiple cancers. Gastric carcinoma tissues show significantly lower PIAS3 levels correlating with larger tumor size and poor differentiation 2. In osteosarcoma, miR-199a-5p promotes tumor growth by targeting PIAS3, leading to STAT3 activation and cell cycle progression 5. PIAS3 loss may also contribute to colorectal cancer pathogenesis through JAK/STAT pathway dysregulation 6. Clinically, PIAS3 demonstrates therapeutic potential in inflammatory diseases. In psoriasis, decreased PIAS3 expression in lesional tissue correlates with disease pathology; PIAS3 restoration inhibits keratinocyte proliferation and inflammatory cytokine production (TNF-α, IL-6, IL-8) via STAT3/NF-κB pathway suppression 7. These findings position PIAS3 as a critical tumor suppressor and therapeutic target for malignancies and inflammatory conditions.