Jianpi Huayu Jiedu Decoction prevents the progression of H. pylori and MNU-induced gastric precancerous lesions by inhibiting ferroptosis and remodeling linoleic acid metabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: Helicobacter pylori (H. pylori) infection is a major risk factor for gastric cancer. Gastric precancerous lesion (GPL) under H. pylori exposure better reflect the clinical trajectory of gastric carcinogenesis. Jianpi Huayu Jiedu Decoction (JHJD), a traditional formula derived from Si-Jun-Zi Decoction, has been widely used in treating gastrointestinal disorders, yet its mechanisms in GPL prevention remains unclear.

AIM OF THE STUDY: This study aimed to assess the therapeutic efficacy of JHJD in an H. pylori and MNU-induced GPL mouse model. A particular focus was placed on uncovering the underlying mechanisms, especially ferroptosis and linoleic acid metabolism, through integrated multi-omics analysis.

MATERIALS AND

METHODS

JHJD was chemically profiled by UPLC-MS/MS. A GPL model was established by H. pylori inoculation combined with MNU exposure Treatment efficacy was assessed by histological examination and biochemical markers. Mechanistic investigations included 16S rRNA gene sequencing and serum metabolomics to assess gut microbiota composition and metabolic alterations. Network pharmacology integrated compound profiling with metabolomic data to predict therapeutic targets. Experimental validations were conducted via Western blotting, TUNEL assay, and transmission electron microscopy.

RESULTS

JHJD significantly improved gastric mucosal pathology, reduced oxidative stress, and restored gut microbial diversity. Metabolomics revealed normalization of linoleic acid metabolism, accompanied by downregulation of pro-oxidative enzymes ALOX15 and CYP1B1. Network pharmacology and molecular assays confirmed that JHJD suppressed ferroptosis by regulating SLC7A11 and GPX4. Furthermore, TUNEL and Western blot analyses indicated enhanced apoptosis of dysplastic gastric cells, suggesting a coordinated regulatory effect on both ferroptosis and apoptosis.

CONCLUSION

JHJD alleviates GPL by modulating linoleic acid metabolism and inhibiting ferroptosis. These findings underscore the multi-target therapeutic potential of JHJD in the prevention of gastric cancer.