AMBRA1 (autophagy and beclin 1 regulator 1) is a multifunctional scaffold protein serving as a substrate-recognition component of DCX(AMBRA1) E3 ubiquitin-ligase complexes. Its primary function involves regulating both cell cycle progression and autophagy through distinct mechanisms. In cell cycle control, AMBRA1 acts as a master regulator of G1/S transition by recognizing phosphorylated D-type cyclins (CCND1, CCND2, CCND3) and mediating their polyubiquitination and degradation through the DCX(AMBRA1) complex 1. This cyclin-D degradation function establishes AMBRA1 as a tumor suppressor that promotes genomic integrity and counteracts tumor growth 1. Additionally, AMBRA1 regulates MYC protein stability through interaction with protein phosphatase 2A (PPP2CA), promoting MYC dephosphorylation and degradation independently of DCX complexes. In autophagy regulation, AMBRA1 functions as a key modulator of the BECN1-PIK3C3 complex, controlling the transition from cytoskeletal tethering to autophagosome nucleation. Upon autophagy induction, AMBRA1 is released from dyneins DYNLL1/DYNLL2 to activate autophagy through Lys-63-linked ubiquitination of BECN1 and ULK1 2. AMBRA1 also regulates mitophagy by facilitating interaction between damaged mitochondria and autophagosomes through PRKN and LC3 proteins, with additional regulation via HUWE1-mediated MFN2 ubiquitination. Clinically, reduced AMBRA1 expression correlates with poor cancer survival and reduced sensitivity to CDK4/6 inhibitors 1. Recent evidence indicates AMBRA1's role in age-related diseases through mitophagy regulation 3, and emerging research demonstrates its involvement in cardiac fibrosis through secretory autophagy-derived extracellular vesicles 4.