Refined Jianpi Huayu Jiedu Decoction Attenuates TAM-Induced Spasmolytic Polypeptide-Expressing Metaplasia (SPEM) by Modulating LCN2-Associated Mitochondrial Dysfunction

Background: Spasmolytic polypeptide-expressing metaplasia (SPEM) is an injury-induced gastric epithelial reprogramming state with limited therapeutic options. Although mitochondrial dysfunction has been implicated in epithelial stress responses, its contribution to SPEM development remains incompletely understood. Traditional herbal decoctions have shown potential in alleviating gastric epithelial injury, yet their underlying mechanisms remain largely unclear. Purpose: This study aimed to investigate whether refined Jianpi Huayu Jiedu Decoction attenuates tamoxifen (TAM)-induced SPEM, with a focus on LCN2-associated mitochondrial dysfunction. Methods: TAM-induced SPEM models were established in mice and gastric epithelial cells. Histological, molecular, and mitochondrial analyses were performed to evaluate SPEM features and epithelial stress responses. UPLC–MS/MS-based chemical profiling, network pharmacology, transcriptomic analysis, and LCN2 knockdown experiments were integrated to explore the underlying regulatory mechanisms. Results: Refined Jianpi Huayu Jiedu Decoction significantly alleviated TAM-induced gastric mucosal injury and suppressed the expression of SPEM-associated markers in vivo and in vitro. JHJD treatment improved mitochondrial function, reduced oxidative stress, and normalized mitochondrial dynamics, accompanied by downregulation of LCN2 expression. Chemical profiling identified multiple bioactive components of JHJD, and integrative analyses combining transcriptomics, network pharmacology, and molecular docking suggested that these components are associated with LCN2-related epithelial stress and mitochondrial regulatory networks. Functional validation further demonstrated that LCN2 knockdown partially recapitulated the protective effects of JHJD on mitochondrial homeostasis and epithelial reprogramming. Conclusions: These findings indicate that refined Jianpi Huayu Jiedu Decoction attenuates TAM-induced SPEM in association with restoration of mitochondrial homeostasis and suppression of LCN2-related stress signaling, providing mechanistic insight into early gastric epithelial reprogramming.