Butyrolactone I blocks the transition of acute kidney injury to chronic kidney disease in mice by targeting JAK1

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 IC₅₀ 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.

Keywords

AKI–CKD transition / butyrolactone I / ferroptosis / JAK1

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