<p>Gastric cancer (GC) remains one of the most common malignant tumors worldwide, with high incidence and mortality rates. Angiopoietin-like protein 1 (ANGPTL1), a member of the ANGPTL family, is known to function as an anti-angiogenic factor and tumor suppressor. However, its role and underlying mechanisms in GC development have not been investigated and require further investigation. Protein expression levels were analyzed using western blotting and immunofluorescence (IF) assays. Cell viability was assessed using the CCK-8 assay, and cell proliferation was evaluated through colony formation assays. Cell migration and invasion were examined using Transwell assays. Angiogenic capacity was determined through tube formation assays. The VEGFA mRNA expression was detected through RT-qPCR. The level of VEGFA was confirmed through ELISA. The tumor size, volume and weight were confirmed through the in vivo assay. The CD31 protein expression was verified though IHC assay. ANGPTL1 was found to be expressed at lower levels in GC cells, and negatively correlated with VEGFA. ANGPTL1 significantly inhibited GC cell proliferation, migration, and invasion. Furthermore, ANGPTL1 suppressed angiogenesis in vitro. Mechanistically, it was observed that ANGPTL1 overexpression reduced VEGFA expression, and ANGPTL1 can interact with VEGFA. Importantly, reintroduction of VEGFA reversed the inhibitory effects of ANGPTL1 on GC progression. Lastly, VEGFA overexpression retarded the tumor growth in vivo. This study demonstrates that ANGPTL1 inhibits the growth, migration, and angiogenesis of GC cells by downregulating VEGFA expression. These findings suggest that ANGPTL1 may serve as a promising therapeutic target for gastric cancer treatment.</p> Graphical Abstract <p></p>