USP1 dependent stabilization of LTA4H drives hepatocellular carcinoma angiogenesis

Tumor angiogenesis is a major driver of hepatocellular carcinoma (HCC) progression, yet the tumor-intrinsic mechanisms that regulate endothelial activation remain incompletely understood. Here, we investigated the role of ubiquitin-specific protease 1 (USP1) in HCC-associated angiogenesis. Spatial transcriptomic analysis revealed a positive association between USP1 expression and vascular formation in HCC tissues. Conditioned medium from USP1-overexpressing HCC cells markedly promoted endothelial proliferation, migration, and tube formation, whereas these effects were attenuated after USP1 silencing. Mechanistically, mass spectrometry and subsequent validation identified leukotriene A4 hydrolase (LTA4H) as a substrate of USP1. USP1 stabilized LTA4H by removing K48-linked polyubiquitin chains and preventing its proteasomal degradation. Functional rescue experiments further showed that LTA4H restoration largely reversed the impaired endothelial activation and angiogenic phenotypes caused by USP1 depletion, accompanied by reactivation of ERK signaling. In vivo, USP1 overexpression enhanced xenograft growth and intratumoral microvessel formation. Collectively, these findings identify the USP1-LTA4H axis as a critical regulator of HCC angiogenesis and provide a mechanistic rationale for targeting this pathway in anti-angiogenic therapy.