Ciclopirox mitigates inflammatory response in LPS-induced septic shock via inactivation of SORT1-mediated wnt/β-Catenin signaling pathway

Objective: Septic shock, the most severe stage of sepsis, is a deadly inflammatory disorder with high mortality. Ciclopirox (CPX) is a broad-spectrum antimycotic agent which also exerts anti-inflammatory effects in human diseases. However, whether CPX can relieve inflammatory response in LPS-induced septic shock remains unclear. Materials and methods: Male C57BL/6 mice LPS were injected intraperitoneally with LPS to simulate septic shock in vivo. RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were subject to LPS treatment to simulate septic shock in vitro. ELISA was applied to detect the level of pro-inflammatory cytokines. Cell viability was assessed by CCK-8 assay. Protein levels was detected by western blotting. Results: CPX enhanced the survival rate and attenuated inflammation in mice with LPS-induced septic shock. Similarly, CPX dose-dependently mitigated LPS-induced inflammation in BMDMs. It was also found that Sortilin 1 (SORT1) was upregulated in both in vivo and in vitro models of LPS-induced septic shock. In addition, SORT1 overexpression counteracted the alleviative effects of CPX on the inflammation response of LPS-challenged BMDMs by activating the Wnt/beta-Catenin signaling. Furthermore, BML-284 (a Wnt/beta-Catenin agonist) treatment also abrogated CPX-mediated moderation of LPS-triggered inflammatory reaction in BMDMs. Conclusions: In sum, we found that CPX protected against LPS-induced septic shock by mitigating inflammation via SORT1-mediated Wnt/beta-Catenin signaling pathway.