Huang-Jin-Shuang-Shen Decoction delays gastric tumorigenesis by suppressing stemness via SCD-mediated fatty acid metabolism modulation.

[BACKGROUND] The Correa cascade posits that gastric cancer (GC) originates from chronic atrophic gastritis. However, the role of fatty acid (FA)-mediated stemness in gastric tumorigenesis remains unclear. Huang-Jin-Shuang-Shen granules (HJSS), a traditional Chinese medicinal formula, may delay gastric tumorigenesis. However, the underlying mechanisms have not been characterized.

[PURPOSE] We investigated the role of stearoyl-CoA desaturase (SCD)-mediated stemness in gastric tumorigenesis and determined whether HJSS granules inhibit stemness by regulating SCD-dependent Wnt signaling to block malignant progression.

[METHODS] We established a rat model of GC induction. Tissues were collected at the intestinal metaplasia (IM), dysplasia, and carcinoma stages to analyze FA metabolism enzyme profiles. In vitro experiments have identified downstream regulatory mechanisms of SCD. The efficacy of HJSS was evaluated based on the histopathological changes, gastric mucosa, gut microbiota, and fecal metabolites. SCD overexpression was used to validate the HJSS targeting of the SCD-Wnt stemness axis.

[RESULTS] SCD demonstrated stepwise upregulation during gastric tumorigenesis. SCD inhibition suppressed cancer stemness and Wnt signaling in vitro, and this effect was reversed by the catalytic product, oleic acid (OA). HJSS ameliorates gastric mucosal pathology, gastric mucosa phenotype, gut microbiota dysbiosis, and metabolic disturbances in rats. HJSS attenuated malignant stemness by targeting SCD-Wnt/β-catenin signaling. SCD overexpression partially counteracted the effects of HJSS.

[CONCLUSION] SCD promotes gastric tumorigenesis by activating Wnt-driven stemness. HJSS inhibits cancer stemness by suppressing the activation of SCD-mediated aberrant Wnt/β-catenin, positioning it as a promising candidate for delaying gastric malignant progression.