Wei_2026_Biomolecules_16_

Hepatocellular carcinoma (HCC) represents one of the most lethal malignancies worldwide and is characterized by profound metabolic reprogramming during its development. Paraoxonase 1 (PON1), a liver-synthesized secretory protein involved in lipid metabolism, has an incompletely defined role in cancer biology. This study aimed to systematically investigate the expression pattern, clinical features, and biological function of PON1 in HCC through an integrated approach combining data mining, RNA-seq and experimental verification. Our results demonstrated that PON1 expression is significantly downregulated in HCC tissues compared with adjacent tissues. Clinically, significant disparities were observed in gender ((2) = 19.305, p < 0.0001), tumor stage ((2) = 18.030, p = 0.0004), and tumor grade ((2) = 13.391, p = 0.0039) between patients with high and low PON1 expression in HCC. Low PON1 expression was associated with poor prognosis (TCGA_LIHC, log-rank: (2) = 9.290, p = 0.0023; ICGC_LIRI, log-rank: (2) = 8.469, p = 0.0036; GSE14520, log-rank: (2) = 9.746, p = 0.0018). Univariate and multivariate Cox regression analyses revealed PON1 as an independent prognostic biomarker. Pathway analysis showed that PON1-positively correlated genes enriched in pathways such as peroxisome and fatty acid degradation, whereas PON1-negatively correlated genes mainly in the cell cycle pathway. Functional experiments confirmed that knockdown of PON1 promoted HCC cell proliferation, migration, invasion and inhibited apoptosis, whereas overexpression of PON1 reversed these malignant phenotypes. Mechanistically, we uncovered that PON1 exerts its tumor-suppressive effects by negatively regulating TANK and CXCL3, key molecules of the NOD-like receptor signaling pathway. In summary, our findings identify PON1 as an independent prognostic biomarker in HCC and demonstrate the tumor-suppressive role of PON1, indicating its potential as a therapeutic target for HCC.