TP53INP2 is a dual-function autophagy regulator and transcriptional coactivator essential for cellular homeostasis. Mechanistically, TP53INP2 functions as a scaffold protein that facilitates autophagosome biogenesis through multiple pathways: it promotes LC3-ATG7 interaction in the cytoplasm 1, recruits Atg8-family proteins (MAP1LC3A, GABARAP, GABARAPL2) to autophagosomal membranes 2, and cooperates with the BECN1-PI3K class III complex to trigger autophagosome development. Acetylation of conserved lysine residues regulates TP53INP2's binding selectivity to Atg8-family proteins, with preferential interaction to GABARAP subfamily members 23. TP53INP2 mediates nuclear-cytoplasmic shuttling of deacetylated LC3 2, directing autophagy machinery to autophagic membranes 1. Disease relevance is substantial: TP53INP2 overexpression ameliorates age-related sarcopenia by enhancing muscle autophagy and mitophagy 4, while elevated TP53INP2 correlates with increased muscle strength and healthy aging in humans 4. Conversely, TP53INP2-mediated autophagy contributes to sunitinib resistance in renal cell carcinoma 5, and suppresses dedifferentiated liposarcoma progression via YAP mitophagy 6. TP53INP2 also regulates α-ketoglutarate metabolism in oligodendrocytes, promoting remyelination 7. These findings establish TP53INP2 as a critical node in autophagy regulation with therapeutic implications across aging, neurodegeneration, and cancer.