Abstract
Objectives: Shen-Ling-Bai-Zhu-San (SLBZS) is a classical traditional Chinese herbal formula with spleen-invigorating and dampness-resolving properties. Recent pharmacological studies suggest its potential to regulate immune and metabolic disorders. Type 2 diabetes mellitus (T2D) and ulcerative colitis (UC) often coexist as comorbidities characterized by chronic inflammation, microbial imbalance, and insulin dysregulation, yet effective therapies remain limited. This study aimed to investigate the molecular mechanisms through which SLBZS may benefit T2D-UC comorbidity. Methods: An integrative multi-omics strategy was applied, combining network pharmacology, structural bioinformatics, and ensemble molecular docking-dynamics simulations. These complementary approaches were used to identify SLBZS bioactive compounds, predict their putative targets, and examine their interactions with disease-related biological networks. Results: The analyses revealed that flavonoids in SLBZS act on the SLC6A14/PI3K-AKT signaling axis, thereby modulating immune responses and improving insulin sensitivity. In addition, SLBZS was predicted to regulate the NF-κB/MAPK signaling pathways, key hubs linking inflammation and metabolic dysfunction in T2D-UC. These dual actions suggest that SLBZS can intervene in both inflammatory and metabolic processes. Conclusions: SLBZS demonstrates promising therapeutic potential for T2D-UC by targeting interconnected immune-metabolic networks. These findings not only provide mechanistic insights bridging traditional therapeutic concepts with modern pharmacology but also establish a theoretical basis for future experimental validation and clinical application.