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

AbstractObjective: 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/β-Catenin signaling. Furthermore, BML-284 (a Wnt/β-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/β-Catenin signaling pathway.Keywords: CiclopiroxLPSseptic shockSORT1Wnt/β-Catenin Disclosure statementNo potential conflict of interest was reported by the authors.Additional informationFundingThis research was supported by Yancheng basic research plan (YCBK202211), Yancheng Medical Innovation Team Fund, and Health Research Project of Jiangsu Province.