Simotang oral liquid alleviates functional dyspepsia-related motility dysfunction through Ca2+-dependent smooth muscle contraction and Nrf2/NF-κB modulation.

Functional dyspepsia (FD) is a disorder of gut-brain interaction involving heterogeneous motor, sensory, immune, and oxidative stress-related mechanisms. Simotang oral liquid (SMT), a traditional Chinese medicine formulation used for dyspeptic and gastrointestinal motility-related symptoms, has not been evaluated with an integrated clinical, functional, and molecular framework. This single-arm prospective pre-post study assessed gastric emptying by the 13C-octanoic acid breath test, gastric electrical activity by electrogastrography, postprandial tolerance by nutrient drink testing, symptom scores, serum biomarkers, and gastric antral tissue markers in patients with FD. FD-like mice were used for charcoal meal transit, smooth muscle strip tension, calcium channel blockade, and mucosal RNA sequencing. Public transcriptomic data from GSE169304 were analyzed to characterize FD-associated duodenal mucosal molecular features. SMT treatment was associated with reduced gastric emptying half-time, improved 3-cpm stability, lower gastric dysrhythmia, reduced Nepean Dyspepsia Index and Gastroparesis Cardinal Symptom Index scores, increased motilin and gastrin levels, lower malondialdehyde, higher superoxide dismutase activity, and lower tumor necrosis factor alpha and interleukin-6 levels. Paired gastric antral biopsy analyses showed increased α-smooth muscle actin and higher phosphorylation ratios of myosin light chain kinase and myosin light chain after SMT treatment. In mice, SMT increased intestinal transit, acetylcholine-induced smooth muscle tension, Cav1.2 abundance, calmodulin fluorescence, and p-MLCK/p-MLC signaling, while nifedipine reduced the SMT-associated phosphorylation changes. Transcriptomic analyses showed enrichment of smooth muscle contraction, calcium signaling, oxidative stress response, and Nrf2-related antioxidant pathways, while protein analyses showed reduced canonical NF-κB activation markers. The data are consistent with Ca2+-dependent smooth muscle contraction as the central motor pathway associated with SMT- related functional improvement in FD, with Nrf2/NF-κB modulation as a microenvironmental regulatory component.