ABSTRACT Acute kidney injury (AKI) is a serious complication of cisplatin chemotherapy, requiring new preventive therapies. Germacrone, a sesquiterpenoid derived from Rhizoma Curcuma , has multiple pharmacological effects, including anti‐inflammatory, antiapoptotic, and antioxidant effects. The current study aimed to investigate the effect and mechanism of germacrone on AKI. Single high‐dose and multiple low‐dose cisplatin‐induced AKI and AKI‐chronic kidney disease (CKD) transition mouse models were used to determine the preventive effect of germacrone, with the mechanism explored in HK‐2 and Raw264.7 cells. A breast cancer tumor‐bearing model was developed to determine whether the nephron‐protective effects of germacrone affect the anticancer properties of cisplatin. Here, we found that germacrone significantly alleviated AKI and fibrosis in cisplatin‐treated mice, as demonstrated by decreased serum creatinine and blood urea nitrogen (BUN) levels and improved renal pathology. Germacrone attenuated cisplatin‐induced apoptosis and inflammation in vivo and in vitro. RNA sequencing revealed that germacrone restored cisplatin‐induced gene dysregulation and regulated inflammation and apoptosis through the PI3K/AKT and Ras/MAPK pathways. Inhibition of these pathways abrogated the renoprotective effect of germacrone in vitro. Moreover, germacrone reduced macrophage activation and induced an M2‐dominant shift in macrophage polarization in the kidneys and Raw264.7 cells via similar pathways. Furthermore, germacrone protected the kidneys without affecting the chemotherapeutic effects of cisplatin on a mouse model of breast cancer. Therefore, germacrone is expected to have universal renoprotective effects across different AKI models and a tumor‐bearing model through similar signaling pathways, suggesting its potential as a clinical adjuvant therapy for reducing nephrotoxicity in patients receiving cisplatin chemotherapy.
Zheng et al. (Thu,) studied this question.