SPSB1 (splA/ryanodine receptor domain and SOCS box containing 1) is a substrate recognition component of SCF-like E3 ubiquitin-protein ligase complexes that mediates proteasomal degradation of target proteins 12. Its primary characterized function involves negatively regulating nitric oxide production in activated macrophages by promoting NOS2 ubiquitination and degradation 2. Beyond immunity, SPSB1 has broader roles across multiple physiological systems. It regulates circadian clock function by targeting RevErbα for degradation 3, and controls ovarian cancer cell survival by destabilizing the cell cycle inhibitor p21 4. Recently, SPSB1 was identified as a key regulator of smooth muscle cell phenotype switching and senescence in thoracic aortic aneurysm pathogenesis, functioning through alternative splicing mechanisms 5. Additionally, SPSB1 regulates adipocyte differentiation by targeting FOG-2 transcriptional cofactor for degradation 6. SPSB1 has been associated with carpal tunnel syndrome susceptibility through exome-wide analysis 7, though it is dispensable for normal spermatogenesis 8. The protein recognizes substrates via a conserved consensus motif (D/E-I/L-N-N-N) in target proteins 9. These findings establish SPSB1 as a versatile E3 ligase adaptor with diverse roles in inflammation, circadian biology, cancer, vascular disease, and metabolic regulation.