Background Septic shock is a critical condition with high mortality and limited treatment options. The optimized Yantiao formula, a traditional Chinese herbal compound, may offer immunomodulatory benefits, but clinical evidence is limited. Methods This randomized controlled trial enrolled 124 patients with septic shock, who were randomly assigned to receive either standard Western therapy alone ( n = 62) or a combination of standard Western therapy and the optimized Yantiao formula ( n = 62). By Day 14, 2 patients in the treatment group and 3 in the control group had died; 119 patients completed the trial (treatment group: n = 60; control group: n = 59). The primary outcome was 28‐day survival. Secondary outcomes included white blood cell (WBC) count, neutrophil percentage (N%), C‐reactive protein (CRP), lactate (LAC), procalcitonin (PCT), heparin‐binding protein (HBP), Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and Sequential Organ Failure Assessment (SOFA) score. Network pharmacology and bioinformatics analyses were performed to explore potential mechanisms. Results The 28‐day survival rate was significantly higher in the treatment group (78.3%, 47/60) compared with the control group (42.8%, 25/59; p value = 0.001). After treatment, the treatment group showed greater reductions in WBC (13.82 ± 3.46 vs. 10.56 ± 2.34 × 10 9 /L, p value < 0.001), N% (89.15 ± 6.29% vs. 80.42 ± 5.87%, p value < 0.001), and CRP (56.34 ± 14.22 vs. 34.23 ± 10.12 mg/L, p value < 0.001). Additionally, APACHE II (17.3 ± 2.1 vs. 13.1 ± 1.9, p value < 0.001) and SOFA scores (9.4 ± 1.6 vs. 6.2 ± 1.4, p value < 0.001) were significantly lower. Levels of TNF‐α ( p value = 0.012), IL‐6 ( p value < 0.001), PCT ( p value < 0.001), and HBP ( p value < 0.001) also showed significant reductions in the treatment group. Network analysis identified 78 overlapping targets enriched in pathways, including AGE‐RAGE signaling and interleukin pathways. Conclusions The optimized Yantiao formula significantly improved survival and reduced inflammation in patients with septic shock, possibly through multitarget immune modulation. These findings support its potential as an adjunctive treatment for septic shock. Trial Registration Chinese Clinical Trial Registry: ChiCTR2100043735
Chen et al. (Wed,) studied this question.