Introduction and Objective: Spasmolytic polypeptide expressing metaplasia (SPEM), which is considered as origin of gastric cancer, is associated with obesity. However, the fundamental determinants and mechanisms underlying obesity-associated SPEM remain poorly understood.Methods: Our metabolomics study analyzed 42 obese patients to assess the association between n-6 polyunsaturated fatty acids (PUFAs) and SPEM. Gastric organoids and mouse models were used to evaluate the effects of n-6 PUFAs supplementation on SPEM formation. Lineage tracing assays and single-cell RNA-sequencing analysis were performed to identify the cellular origins of SPEM.Results: High levels of n-6 PUFAs were significantly associated with SPEM in obese patients. Supplemental n-6 PUFAs induced SPEM derived from quiescent Lgr5+ stem cells (ISCs) at the mucosal base. Mechanistically, downregulated stearyl CoA desaturase 1 (SCD1) activated the ERK pathway, promoting SPEM development. SCD1 was found to bind Prohibitin 1 (PHB1), enhancing PHB1’s degradation via ubiquitin E3 ligase tripartite-motif-containing 21 (TRIM21), thereby suppressing the ERK pathway. A novel diagnostic model based on SCD1, PHB1, and ERK expression was developed, and dietary intervention with low-linoleic acid or ERK inhibition effectively reduced SPEM.Conclusion: Dietary enrichment with n-6 PUFAs represents a new aetiology of SPEM, driven by the activation of the ERK pathway via the SCD1-PHB1-TRIM21/ERK axis. Strategies targeting n-6 PUFAs dietary intervention and the SCD1-PHB1-TRIM21/ERK pathway offer promising therapeutic potential for SPEM.
X. Wen: None. H. You: None. X. Wang: None. H. Chen: None. L. Bu: None. S. Qu: None.
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