SORBS3 (sorbin and SH3 domain containing 3) is a multi-functional adaptor protein with two isoforms (α and β) that regulate cytoskeletal organization and cell signaling. SORBS3-α promotes actin stress fiber formation [UniProt], while SORBS3-β facilitates cell spreading and JNK/SAPK activation [UniProt]. At the molecular level, SORBS3 functions through protein-protein interactions via its SH3 domains and serves as a cytoskeletal adaptor regulating focal adhesion dynamics and cell adhesion [GO annotations]. Mechanistically, SORBS3 acts as a negative regulator of autophagy by competing with YAP1/TAZ for angiomotin binding, thereby suppressing autophagosome formation 12. Additionally, SORBS3-β suppresses Wnt/β-catenin signaling by recruiting UBA1 to promote β-catenin ubiquitination and degradation 3. Clinically, SORBS3 demonstrates tumor-suppressive functions. SORBS3-β expression is reduced in cervical cancer and suppresses lymph node metastasis by inhibiting lymphangiogenesis 3. Similarly, SORBS3 is downregulated in lung adenocarcinoma and hepatocellular carcinoma, where its loss correlates with enhanced IL-6/STAT3 signaling and poor prognosis 45. SORBS3 methylation increases in obesity and is reversed by weight loss surgery, correlating with insulin sensitivity 6. Pathologically, excessive lactate-induced SORBS3 lactylation triggers phase separation promoting extracellular vesicle sorting, contributing to overtraining-induced hepatic fibrosis 7.