PSIP1 (PC4 and SRSF1 interacting protein 1), also known as LEDGF/p75, is a multifunctional transcriptional coactivator and chr9-associated protein with diverse roles in cellular homeostasis and disease. As a primary function, PSIP1 acts as a transcriptional coregulator involved in transcription elongation through its interaction with elongation machinery via conserved TND-TIM interaction modules 1. Mechanistically, PSIP1 maintains genome integrity by reducing R-loop accumulation at transcription sites through interactions with PARP1 and R-loop homeostasis proteins; PSIP1 depletion causes R-loop and DNA damage accumulation at gene promoters, increasing sensitivity to PARP inhibitors 2. Additionally, PSIP1 functions as a lentiviral integration cofactor essential for HIV-1 replication 3, and serves as an L-arginine sensor promoting T cell survival and anti-tumor responses 4. Disease relevance encompasses multiple malignancies: PSIP1 is a dependency factor in KMT2A-rearranged leukemia and correlates with poor prognosis in hepatocellular carcinoma through c-Myc pathway activation 5; conversely, it exhibits tumor suppressor functions in T-ALL where loss accelerates disease initiation 6. Clinically, PSIP1 dysregulation in prostate and breast cancers positions it as an emerging therapeutic target 7, while T cell exhaustion-related PSIP1 expression predicts osteosarcoma prognosis 8.