Lipidomics and single-cell transcriptomics uncover aberrant lipid metabolism in metaplasia lesions during gastric carcinogenesis.

[BACKGROUND] Gastric intestinal metaplasia (GIM) is a precancerous lesion that elevates gastric cancer risk. Our prior single-cell RNA sequencing (scRNA-seq) analysis implied aberrant lipid metabolism in GIM. We also established a Ddit4-deficient mouse model that developed severe gastric metaplasia lesions upon Helicobacter pylori (H. pylori) infection. This study aims to define the lipid signatures of metaplasia lesions in gastric carcinogenesis.

[METHODS] We performed lipidomic analysis of gastric tissues from H. pylori-infected Ddit4 and wild-type (WT) mice, and from human GIM and chronic non-atrophic gastritis (CNAG) samples. scRNA-seq data were reanalyzed to identify lipid metabolism-related gene expression during GIM progression. The therapeutic effects of lipid inhibitors sulfosuccinimidyl oleate sodium (SO), TVB3664 and fenofibrate, were evaluated in patient-derived gastric cancer organoids and in a tamoxifen (TAM)-induced gastric metaplasia mouse model. Immunohistochemistry, immunofluorescence, and BODIPY 505/515 staining were also conducted.

[RESULTS] Lipidomic profiling revealed a marked increase in triglyceride (TG) levels in Ddit4 mice with gastric metaplasia. Similarly, human GIM tissues showed elevated TG content compared to CNAG. BODIPY staining confirmed lipid droplet (LD) accumulation in GIM. GSEA analysis of scRNA-seq data indicated upregulation of TG metabolism and synthesis pathways in GIM. Key genes involved in TG synthesis (DGAT1, MOGAT2, MOGAT3) and fatty acid (FA) transport (FABP1, FABP2, SLC27A4) were significantly elevated in GIM. Notably, DGAT1 protein levels were substantially upregulated in human GIM tissues relative to CNAG controls. In contrast, certain membrane lipids like lysophosphatidylcholine (LPC) subclasses were reduced in GIM. FA transport inhibitor SO and synthesis inhibitor TVB3664 suppressed gastric cancer organoid growth. In mice, TVB3664 and fenofibrate alleviated gastric pathology including inflammation and metaplasia.

[CONCLUSIONS] Our study reveals a distinct lipid signature in gastric metaplasia characterized by TG and LD accumulation, providing novel therapeutic insights into targeting lipid metabolism to prevent GIM malignant transformation and reduce cancer risk.