Ethnopharmacological relevance: Shenling Baizhu Powder (SBP), a classic traditional Chinese medicine formula documented in Taiping Huimin Heji Jufang, has been widely used in the management of gastrointestinal disorders. Pyrotinib, a tyrosine kinase inhibitor employed in cancer treatment, is frequently associated with chemotherapy-induced diarrhea.
Purpose: This study aimed to investigate the effect of pyrotinib on intestinal chloride secretion and to evaluate the therapeutic potential and underlying mechanism of SBP against pyrotinib-induced diarrhea.
Methods: Twenty-four rats were randomly divided into four groups: control, SBP, pyrotinib, and pyrotinib + SBP. Intestinal chloride secretion and channel activity were assessed using the Ussing chamber system. Network pharmacology analysis was performed to predict the signaling pathways involved in SBP-mediated cystic fibrosis transmembrane conductance regulator (CFTR) regulation. A two-sample Mendelian randomization (MR) analysis was further conducted to examine causal relationships between key targets identified through network pharmacology and CFTR, using summary-level genetic data. Western blot analysis was used to validate the predicted signaling pathway.
Results: SBP administration significantly alleviated diarrhea symptoms and restored electrolyte homeostasis in pyrotinib-treated rats. Ussing chamber experiments using rat ileal tissues and T84 cell models demonstrated that SBP effectively inhibited chloride ion secretion through suppression of the CFTR channel. Analysis based on network pharmacology revealed SBP as a potential regulator of CFTR, acting through Epidermal Growth Factor (EGF)-mediated cyclic adenosine monophosphate (cAMP) signaling. MR analysis provided supporting evidence for a causal effect of EGF on CFTR (p = 0.039). Experimental validation confirmed that SBP downregulated EGF and cAMP expression, consequently attenuating CFTR-mediated chloride secretion.
Conclusion: SBP ameliorates pyrotinib-induced diarrhea by modulating the EGF-cAMP-CFTR signaling axis, thereby inhibiting intestinal chloride secretion and restoring electrolyte balance. In addition to confirming its therapeutic effect, this study reveals a previously unrecognized mechanism whereby SBP downregulates EGFR-dependent CFTR activation, offering a mechanistic explanation for its antidiarrheal properties. These findings not only highlight the mechanistic novelty of SBP in the context of targeted-therapy-associated diarrhea but also provide a scientific foundation supporting its clinical application and future translational development.
Keywords: CFTR; Chloride ion secretion; Pyrotinib-induced diarrhea; Shenling baizhu powder.
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