SPSB2 functions as a substrate recognition component of an ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin ligase complex that mediates ubiquitination and proteasomal degradation of target proteins 1. Its primary role is negatively regulating nitric oxide (NO) production by mediating ubiquitination and degradation of inducible NOS2 (iNOS), thereby limiting cellular toxicity in activated macrophages 2. SPSB2 acts as a bridge linking iNOS with ECS complex components ELOC and CUL5 2. Beyond NO regulation, SPSB2 targets diverse substrates: it inhibits hepatitis C virus replication by degrading the viral NS5A protein 3, and clears iNOS protein aggregates formed after Hsp90 inhibition through ubiquitin-proteasome-mediated degradation 4. Clinically, SPSB2 expression correlates with poor prognosis in hepatocellular carcinoma patients and is associated with tumor proliferation, invasion, and metastasis 5. The SPRY domain of SPSB2 recognizes specific substrate motifs (exemplified by DINNN sequences in iNOS) 6, making SPSB2 a target for therapeutic inhibition through cyclic peptide antagonists designed to augment NO production for antimicrobial and anticancer applications 7. MDM2-mediated degradation of SPSB2 stabilizes iNOS and promotes M1 macrophage inflammatory responses 8.