Elaidic acid suppresses hepatocellular carcinoma growth through modulating the production of intestinal <i>Ligilactobacillus murinus</i> -derived spermidine

Dietary intervention provides a novel approach for cancer therapy. Elaidic acid (EA), which accounts for 80-90% of total trans fatty acids in foods, has recently been found to exert anti-tumor effects. However, the biological functions and underlying mechanisms of EA remain elusive in hepatocellular carcinoma (HCC). In this study, targeted fatty acid metabolomics demonstrated that among 44 types of fatty acids, the concentration of EA decreased most significantly when comparing plasma from HCC patients with plasma from healthy people. Through <i>in vivo</i> assays using HCC orthotopic and xenograft mouse models, we further revealed that dietary EA attenuates HCC growth. Notably, when gut microbiota was depleted using a cocktail of antibiotics, the anti-tumor effect of EA was diminished, confirming that EA suppresses HCC tumor growth by modulating gut microbiota. Mechanistically, analysis of 16S ribosomal RNA sequencing showed that dietary EA markedly increases the abundance of intestinal <i>Ligilactobacillus murinus (L. murinus)</i>. Subsequent untargeted metabolomic sequencing analysis further demonstrated that dietary EA drives the production of <i>L. murinus</i>-derived spermidine (SPD), which attenuates HCC growth <i>in vitro</i> as well as <i>in vivo</i>. The observed impact correlated with the phosphorylation of p38 MAPK and the upregulation of biomarkers pertinent to apoptosis and proliferation, including tumor protein 53, bcl-2-associated X protein, and cysteine-requiring aspartate protease 3. Taken together, our findings highlight the important role of intestinal <i>L. murinus</i>-derived SPD in EA-mediated HCC suppression, thereby offering a promising dietary strategy for HCC treatment.