肺腺癌（LUAD）是全世界癌症相关死亡的主要原因，但其潜在的分子机制仍不清楚。转录因子 (TF) 特异性蛋白 1 (SP1) 在包括 LUAD 在内的各种癌症的发展中发挥着至关重要的作用。最近的研究表明，主转录因子可能形成相分离的大分子缩合物，以促进超级增强子（SE）组装和癌基因表达。在这项研究中，我们证明了 SP1 会发生相分离，并且其 DNA 结合域中的锌指 3 对于这一过程至关重要。通过目标下的裂解

Lung adenocarcinoma (LUAD) is the leading cause of cancer-related death worldwide, but the underlying molecular mechanisms remain largely unclear. The transcription factor (TF) specificity protein 1 (SP1) plays a crucial role in the development of various cancers, including LUAD. Recent studies have indicated that master TFs may form phase-separated macromolecular condensates to promote super-enhancer (SE) assembly and oncogene expression. In this study, we demonstrated that SP1 undergoes phase separation and that its zinc finger 3 in the DNA-binding domain is essential for this process. Through Cleavage Under Targets & Release Using Nuclease (CUT&RUN) using antibodies against SP1 and H3K27ac, we found a significant correlation between SP1 enrichment and SE elements, identified the regulator of the G protein signaling 20 (RGS20) gene as the most likely target regulated by SP1 through SE mechanisms, and verified this finding using different approaches. The oncogenic activity of SP1 relies on its phase separation ability and RGS20 gene activation, which can be abolished by glycogen synthase kinase J4 (GSK-J4), a demethylase inhibitor. Together, our findings provide evidence that SP1 regulates its target oncogene expression through phase separation and SE mechanisms, thereby promoting LUAD cell progression. This study also revealed an innovative target for LUAD therapies through intervening in SP1-mediated SE formation.