Coordinated gene expression within persistent STAT3-associated chromatin conformations contributes to hepatocellular carcinoma progression [CHIP-seq]

p-STAT3 has emerged as a critical modulator of hepatocellular carcinoma (HCC) progression; however, its role in 3D chromatin architecture and the expression of genes linked to HCC aggressiveness remains largely unexplored. Here, we elucidate the function of p-STAT3 in establishing stable regulatory regions known as FIREs, characterized by highly active interactions and the potential to alter topologically associated domains (TADs). Our results demonstrate that expression of genes located within FIREs is highly correlated, and upregulation, these genes play a crucial role in driving phenotypes, including HCC invasion and tube formation. Notably, p-STAT3-associated FIREs maintain chromatin activation despite pharmacological interventions targeting STAT3, suggesting a mechanism that failure to suppress the expression of genes associated with HCC aggressiveness leads to drug resistance. These findings provide novel insights into how the 3D genome structure associated with p-STAT3 promotes HCC progression and drug resistance, highlighting the therapeutic potential of targeting 3D chromatin dynamics in HCC.