Abstract
Chronic kidney disease (CKD) is a disease that affects more than 850 million people. Acute kidney injury (AKI) is a common cause of CKD, and blocking the AKI-CKD transition shows promising therapeutic potential. Herein, we found that butyrolactone I (BLI), a natural product, exerts significant nephroprotective effects, including maintenance of kidney function, inhibition of inflammatory response, and prevention of fibrosis, in both folic acid- and ureteral obstruction-induced AKI-CKD transition mouse models. Notably, BLI showed greater blood urea nitrogen reduction and anti-inflammatory effects than telmisartan. Bioinformatics analysis and target confirmation assays suggested that BLI directly binds to JAK1, and kinase inhibition assay confirmed it is a potent JAK1inhibitor with an IC(50) of 0.376 µM. Experiments in JAK1-knockdown mice also proved that BLI targets JAK1 to work. Furthermore, BLI demonstrated nephroprotective effects and safety comparable to ivarmacitinib, the well-known JAK1 inhibitor. Mechanistically, BLI targets JAK1 and inhibits its phosphorylation and JAK-STAT activation, subsequently regulating the downstream signaling pathways to inhibit reactive oxygen species production, inflammation, and ferroptosis, thereby preventing the occurrence of kidney fibrosis and blocking the AKI-CKD transition process. This study demonstrates for the first time that BLI is a JAK1 inhibitor and a promising candidate for delaying CKD progression, which warrants further investigation.