PER1 reduces HIF-1α nuclear accumulation and modulates vascular remodeling in hepatocellular carcinoma

The core clock gene period 1 (PER1) has been reported to possess tumor-suppressive functions; however, its role in regulating tumor vascular abnormalities in hepatocellular carcinoma (HCC) remains incompletely understood. Here, we integrated bioinformatics analysis with validation using clinical HCC specimens, cell-line experiments, and mouse models to investigate the role of PER1 in vascular structure-related phenotypes, angiogenesis-related factor expression, and hypoxia-inducible factor-1α (HIF-1α) signaling. PER1 was significantly downregulated in HCC tissues, and low PER1 expression was associated with poor patient prognosis. Restoration of PER1 expression inhibited HCC cell growth. Mechanistically, PER1 interacted with HIF-1α at the protein level and reduced its nuclear accumulation without markedly altering HIF-1α mRNA or total protein abundance. This change was accompanied by an angiogenesis-related factor profile characterized by increased TSP-1 and TIMP-2 expression and decreased VEGFA, TGF-β, SDF-1, and FGF-2 expression. Histological analyses further showed that PER1 overexpression was associated with increased CD31-positive vascular structures, enhanced α-SMA-positive perivascular/pericyte-like components, and more continuous collagen IV deposition, whereas PER1 knockdown produced the opposite effects. These findings indicate that PER1 participates in vascular structural remodeling in HCC. Collectively, our study suggests that PER1 modulates HIF-1α-associated angiogenic signaling and vascular structural remodeling, providing new insight into the interaction between circadian rhythm regulation and the HCC vascular microenvironment.