Icaritin Improves the Hematopoiesis-Supportive Function of MSCs via A PRDX1–MAPK Axis After Chemotherapy

The alleviation of chemotherapy-induced myelosuppression is an integral part of sustained and effective cancer therapy. Although the role of the hematopoietic microenvironment in the regulation of hematopoietic stem/progenitor cells (HSPCs) has been widely studied, no drugs that improve hematopoiesis by targeting and modulating the hematopoietic microenvironment have been used clinically. Here, we show that the active small molecule icaritin (ICT) from the Chinese herb Epimedium brevicornum Maxim effectively alleviates chemotherapy-induced hemocytopenia in both mouse and zebrafish models. We demonstrated that ICT enhanced the number and hematopoietic function of HSPCs and that the beneficial effects of ICT occurred indirectly. Single-cell sequencing analysis confirmed that the target cells of ICT in the bone marrow microenvironment were mesenchymal stromal cells (MSCs). In addition, peroxiredoxin 1 (PRDX1) was identified as a direct target of ICT. Furthermore, ICT stimulated MSCs to express the effector molecule C–X–C motif chemokine ligand 12 (CXCL12) through the PRDX1–reactive oxygen species (ROS)–mitogen-activated protein kinase (MAPK) signaling axis, thereby increasing the number and function of HSPCs. These results suggest that ICT is a promising compound for achieving targeted modulation of the hematopoietic microenvironment to restore hematopoiesis after chemotherapy.