Ulcerative colitis (UC) is considered as a global health issue, with a notable surge in incidence over the past two decades (Pravda, 2019). This chronic inflammatory bowel disease (IBD) predominantly impacts the colorectal mucosa and submucosa. Current mainstream treatments, including 5-aminosalicylic acid, steroids, immunosuppressants, and biologic agents, are widely used (Baumgart and Sandborn, 2007); however, they frequently entail considerable side effects (Berends et al., 2019). Additionally, biologic therapies are not only expensive but also carry risks of potential immunogenicity and drug resistance. Consequently, the development of effective, low-toxicity, and affordable treatments for UC remains a crucial need in contemporary gastroenterology research (Daguet et al., 2016).

Over the past decade, Traditional Chinese Medicine (TCM) has demonstrated significant promise for managing chronic diarrhea, characterized by balanced therapeutic effects and a favorable safety profile (Wan et al., 2014). According to TCM theory, chronic diarrhea is related to spleen deficiency. Buzhongyiqi Decoction (BZYQD) is a classic prescription from the Chinese medical text "Pi Wei Lun," is widely used to address this issue.‌ BZYQD has the effects on regulating the spleen-stomach function, replenishing Qi to raise yang, and removing heat with sweet and warm properties (Hu et al., 2023). This prescription includes Astragalus mongholicus Bunge (honeyed), Actaea heracleifolia (Kom.) J.Compton, Atractylodes macrocephala Koidz.(wheat-fried), Glycyrrhiza uralensis Fisch. (honeyed), Codonopsis pilosula (Franch.) Nannf., Angelica sinensis (Oliv.) Diels, Bupleurum chinense DC., and Citrus reticulata Blanco (Lu et al., 2021; Wang et al., 2021). The plant names have been verified in MPNS (http://mpns.kew.org) on April 24th, 2025. Experimental data show that BZYQD ameliorated 5-fluorouracil-induced intestinal mucositis in mice through inhibiting pro-inflammatory cytokine release. (Gou et al., 2016). Nevertheless, its precise mechanisms and molecular targets remain unclear.

Buzhongyiqi Granules (BZYQ), a modern pharmaceutical formulation derived from BZYQD, are characterized by a brown color and a flavor profile blending sweetness, mild bitterness, and spiciness. The granules primarily contain the original ingredients in BZYQD, supplemented with Ziziphus jujuba Mill., Zingiber officinale Roscoe, and pharmaceutical excipients. BZYQ is clinically employed to strengthening the spleen and replenishing Qi, raising Yang and alleviating depression symptoms, with indications including spleen-stomach weakness, Qi deficiency and fatigue, anorexia, abdominal distension, and chronic diarrhea (Zu et al., 2023). Clinical trials have demonstrated that BZYQ alleviates diarrhea symptoms in UC patients, with efficacy both as monotherapy and in combination with standard treatments (Tu and Chen, 2008). However, current research on BZYQ faces several limitations: (1) the chemical composition of BZYQ remains incompletely characterized, and its pharmacodynamic material basis and bioactive metabolites are poorly defined; (2) the treatment ofUC with BZYQ primarily relies on clinical observations, with a scarcity of animal experiments to support its efficacy. This lack of standardized and laboratory indicators hampers a comprehensive understanding of BZYQ's therapeutic effects; (3) The mechanisms underlying the treatment of UC with BZYQ is not yet fully understood (Kang et al., 2021).

In the current work, we integrated medical chemistry, bioinformatics, and network pharmacology methods to elucidate the chemical constituents and systemically absorbed components of BZYQ, and identified potential molecular targets for its treatment of UC. Simultaneously, we employed molecular docking, animal models, and primary cell culture to validate the molecular and cellular mechanisms pertinent to BZYQ's therapeutic efficacy. Our findings not only unveil the material basis and cellular immunological mechanisms of BZYQ in UC treatment, but also facilitate the further development and clinical application of this formulation.