Uncovering the Mechanisms of Cinnamic Acid Treating DiabeticNephropathy based on Network Pharmacology, Molecular Docking, andExperimental Validation

Background: Cinnamic acid (Cinn) is a phenolic acid of Cinnamomum cassia (L.) J. Presl. that can ameliorate diabetic nephropathy (DN). However, comprehensive therapeutic targets and underlying mechanisms for Cinn against DN are limited. Objective: In this study, a network pharmacology approach and in vivo experiments were adopted to predict the pharmacological effects and mechanisms of Cinn in DN therapy Methods: The nephroprotective effect of Cinn on DN was investigated by a streptozotocininduced diabetes mellitus (DM) mouse model. The protein-protein interaction network of Cinn against DN was established by a network pharmacology approach. The core targets were then identified and subjected to molecular docking with Cinn. Results: Cinn treatment effectively restored body weight, ameliorated hyperglycemia, and reduced kidney dysfunction markers in DM mice, also demonstrating a reduction in tissue injury. Network pharmacology analysis identified 298 DN-Cinn co-target genes involved in various biological processes and pathways. Seventeen core targets were identified, eight of which showed significant differential expression in the DN and healthy control groups. Molecular docking analysis revealed a strong interaction between Cinn and PTEN. Cinn treatment downregulated the PTEN protein expression in DM mice. Conclusion: This study revealed the multi-target and multi-pathway characteristics of Cinn against DN. Cinn improved renal pathological damage of DN, which was related to the downregulation of PTEN.