TCM formula optimization for treating diabetic peripheral neuropathy: Network pharmacology, machine learning, and experimental verification

Background: Diabetic peripheral neuropathy (DPN) is a common chronic complication of diabetes mellitus that significantly impairs patients’ quality of life. Traditional Chinese Medicine (TCM), as a major component of complementary and alternative medicine, has accumulated numerous effective formulas for the clinical management of DPN. However, systematic approaches for optimizing TCM formulas remain limited. Objective: To establish a pathway-oriented approach for TCM formula optimization and to evaluate the efficacy and mechanisms of the optimized formula in DPN. Methods: We developed 2 formula optimization algorithms that defined pathway-oriented herbal correlation (HC) and herbal contribution (HO) to screen and construct a new herbal formula, Qihongtongbi (QHTB), for treating Qi deficiency and blood stasis syndrome complicated with DPN. An animal experiment was subsequently conducted to evaluate the therapeutic effectiveness of QHTB. A total of 32 specific-pathogen-free ob/ob mice (18–20 g) were randomly divided into 4 groups: model, Mudan Granules (MDG), QHTB low- and high-dose groups ( n = 8). Ten male C57BL/6J mice (18–20 g) served as the control group. Metabolomics analysis was further employed to elucidate the biological mechanisms underlying the effects of QHTB. Results: Based on our previous study on TCM medication patterns for treating DPN, 22 candidate herbs were selected for formula optimization. The top 5 candidate herbs (total HC = 25.24 × 10 5 ) exhibited HC values comparable to those of MDG (total HC = 26.1 × 10 5 ). These herbs were Carthamus tinctorius L. (HC = 5.40 × 10 5 ), Astragalus mongholicus Bunge (HC = 5.23 × 10 5 ), Salvia miltiorrhiza Bunge (HC = 5.15 × 10 5 ), Commiphora myrrha (T. Nees) Engl. (HC = 5.02 × 10 5 ), and Glycyrrhiza glabra L. (HC = 4.44 × 10 5 ). HO analysis showed that the cumulative HO of these 5 herbs exceeded 50%. In vivo experiments demonstrated that, compared with the model group, QHTB had significantly lower blood glucose ( P < 0.05), enhanced nerve conduction velocity ( P < 0.01), improved nociceptive hypersensitivity ( P < 0.01), and ameliorated sciatic nerve morphology, with efficacy comparable to MDG. Serum and fecal metabolomics further revealed that QHTB exerted multipathway regulatory effects, among which nicotinate and nicotinamide metabolism represented a key mechanism. Conclusion: In summary, this study provides a methodological reference for the systematic optimization of TCM formulas.