TIPRL (TOR signaling pathway regulator-like) is a regulatory protein that functions primarily as an allosteric inhibitor of protein phosphatases PP2A and PP4. Structurally, TIPRL adopts a novel fold with a central antiparallel beta-sheet core and contains a conserved cleft that preferentially binds the unmodified C-terminal tail of PP2A 1. The protein inhibits PP2A catalytic activity by blocking the phosphatase's active site and coordinates with latency chaperone α4 to disassemble active holoenzymes in a methylation-dependent manner 2. TIPRL negatively regulates PP4 activity by inhibiting formation of the active PP4C:PP4R2 complex, thereby promoting H2AX phosphorylation and enhancing DNA damage response signaling 3. In cancer contexts, TIPRL is significantly upregulated in hepatocellular carcinoma and non-small cell lung cancer, where it contributes to tumor progression through multiple mechanisms 45. In lung cancer stem cells, TIPRL maintains stemness and survival by binding CaMKK2 and activating a CaMKK2-CaMK4-CREB feedback loop 5. In hepatocellular carcinoma, TIPRL promotes TRAIL resistance by facilitating MKK7-PP2Ac interactions and preventing prolonged JNK activation 6. Pan-cancer analysis reveals TIPRL overexpression correlates with poor prognosis and genomic instability across multiple tumor types 7.