CXCR2 promotes tacrolimus-related cardiotoxicity via activating the Src-mediated PI3K/Akt/mTOR pathway.

Tacrolimus is produced through fermentation by the Streptomyces tsukubaensis strain and its related cardiotoxicity is a clinical problem that can not be ignored and needs to be solved in pediatric patients. However, the mechanism of tacrolimus-related cardiotoxicity in pediatric patients remain unknown. This study aims to explore potential drug targets for tacrolimus-related cardiotoxicity and conduct experimental therapeutic research. Transcriptomics, bioinformatics, molecular biology, pathological staining were used to explore potential drug targets for tacrolimus-related cardiotoxicity in wistar rats and knockout mice. In the animal models of tacrolimus-related cardiotoxicity, myocardial fibrosis and epithelial-mesenchymal transition (EMT) occurred and CXCR2, Src-mediated PI3K/Akt/mTOR pathway were activated (P < 0.05 or P < 0.01). CXCR2 antagonist or CXCR2 knockout inactivated Src-mediated PI3K/Akt/mTOR pathway, meanwhile alleviated myocardial fibrosis and EMT (P < 0.05 or P < 0.01). The present study demonstrates that CXCR2 promotes tacrolimus-related cardiotoxicity via activating the Src-mediated PI3K/Akt/mTOR pathway for the first time. CXCR2 antagonist may be used as intervention for potential tacrolimus-related cardiotoxicity via inactivating the Src-mediated PI3K/Akt/mTOR pathway to alleviate myocardial fibrosis and reverse myocardial EMT.