Kumatakenin drives renal and hepatic fibrosis via macrophage-to-myofibroblast transition.

Macrophage-to-myofibroblast transition (MMT) is a pivotal driver of fibrogenesis and disease progression in both chronic kidney disease (CKD) and chronic liver disease (CLD). Kumatakenin, a bioactive compound extracted from traditional medicinal plants, has been shown to exhibit significant protective effects in various inflammatory and neoplastic diseases. However, there remains a considerable gap in understanding whether prolonged or high-dose usage of Kumatakenin could potentially induce adverse effects. This study demonstrates that Kumatakenin exacerbates renal and hepatic fibrosis and induces nephrotoxicity and hepatotoxicity by promoting MMT and the excessive deposition of extracellular matrix (ECM). Mechanistically, Kumatakenin regulates MMT in association with the activation of the Smad3 signaling, which plays a crucial role in fibrogenesis. Furthermore, the depletion of macrophages significantly prevents both nephrotoxicity and hepatotoxicity induced by Kumatakenin, highlighting the pivotal role of macrophages in this process. Therefore, our findings strongly suggest that Kumatakenin effectively modulates MMT, exacerbating CKD and CLD, and the severity of renal and hepatic fibrosis. These results provide a critical theoretical basis for thoroughly evaluating and considering the safety profile of Kumatakenin in clinical applications, emphasizing the need for caution in its therapeutic use.