Sodium Danshensu Attenuates Renal Ischemia-Reperfusion Injury by Suppressing STAT3-Driven Cytokine Signaling and Apoptosis.

OBJECTIVE: To evaluate the renoprotective effects and underlying molecular mechanisms of sodium danshensu (SDSS) in renal ischemia-reperfusion (RIR) induced acute kidney injury. METHODS: Network pharmacology, Weighted Gene Co-expression Network Analysis, single-cell RNA sequencing and machine learning algorithms were integrated to systematically identify SDSS's potential therapeutic targets in RIR. Molecular docking was also employed to confirm key target interactions. Target validation was performed both in vivo and in vitro. In vivo, a rat RIR model was established by occluding bilateral renal arteries, and SDSS (20 mg•kg-1•d-1) was administered intraperitoneally for 28 d. Renal injury was evaluated by HE and TTC stainings, while the expression of signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3 (p-STAT3), BCL2 associated X (BAX), and caspase 3 (CASP3) in kidney tissues was detected via immunofluorescence, Western blot, and qRT-PCR. In vitro, hypoxia/reoxygenation-treated HK-2 cells were used to assess the protective effect of SDSS (13 µg/mL), with cell viability and apoptosis measured by cell counting kit-8 and flow cytometry, respectively, and STAT3 phosphorylation levels examined by Western blot, further confirming the involvement of the STAT3 pathway. RESULTS: The results of network pharmacology and multiomics analysis identified STAT3, P-STAT3, RELA proto-oncogene (RELA), C-C motif chemokine ligand 2 (CCL2), tumor necrosis factor (TNF), BAX, and CASP3 as therapeutic targets involved in inflammation, apoptosis and immune regulation during RIR progression. More importantly, SDSS significantly reduced the infarction volume and preserved tissue integrity in vivo (P<0.01). RIR upregulated STAT3, BAX, and CASP3 expressions, which SDSS treatment effectively reversed both in vivo and in vitro (P<0.01). CONCLUSION: SDSS alleviates RIR injury by suppressing inflammatory and apoptotic signaling, primarily through downregulation of STAT3, BAX, and CASP3, providing new insights into its therapeutic mechanism and potential clinical application.