Integrating Network Pharmacology to Investigate Cinnamaldehyde's Protective Effect Against Oxaliplatin-induced Neurotoxicity

This study investigates the protective effects of cinnamaldehyde (CA) against oxaliplatin (OXA)-induced damage in rat dorsal root ganglion (DRG) cells. The pharmacological activities of CA were analyzed, and its potential targets, along with those of its metabolites, were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), Integrative Pharmacology-based Network Computational Research Platform of Traditional Chinese Medicine (TCMIP), and PharmMapper platforms. The CCK-8 assay is used to determine the optimal concentrations of drugs, while malondialdehyde (MDA) assays are applied to assess the level of lipid peroxidation. Intracellular levels of Fe²⁺ and reactive oxygen species (ROS) were quantified using fluorescent probes. The impact of CA on protein expression levels, including p-STAT3, XCT, and GPX4, in OXA-treated DRG cells was examined via immunoblotting. Network pharmacology analysis identified 14 overlapping targets among "CA-neuropathic pain (NP)-ferroptosis". Experimental results demonstrated that a 24 h treatment with 4.0 µmol/L CA yielded optimal effects, significantly reducing MDA, Fe²⁺, and ROS levels in DRG cells (P < 0.05). Furthermore, CA treatment downregulated the expression of JAK2, STAT3, p-STAT3, TFRC, ErbB-1, and nuclear factor-kappa B (NF-κB) (P < 0.05) while upregulating XCT, GPX4, and FTH1 expression (P < 0.05). These findings suggest that CA mitigates OXA-induced damage in DRG cells by inhibiting the JAK2/STAT3 signaling pathway and activating the SLC7A11-GSH-GPX4 axis.