A novel Keap1-Nrf2 inhibitor 6K delays the progression of AKI-to-CKD by mitigating maladaptive repair.

Severe or recurrent acute kidney injury (AKI) is a critical risk factor for chronic kidney disease (CKD) progression, characterized by irreversible fibrosis and limited therapeutic options. Maladaptive repair in proximal tubular epithelial cells (PTECs) during AKI-to-CKD progression is crucial, with the oxidative stress (OS)-ferroptosis axis emerging as a potential therapeutic target. Nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of redox balance and ferroptosis, is essential for cellular homeostasis, but its role in PTECs maladaptive repair is unclear. In this study, we employed Nrf2 knockout (KO) mice to establish an AKI-to-CKD model through bilateral ischemia-reperfusion injury (bIRI). Nrf2 deficiency significantly exacerbated renal fibrosis, OS markers (H2O2, NOX4, 8-OHdG), and ferroptosis indicators (4-HNE, MDA, ACSL4), while concurrently suppressing antioxidant enzyme activity (SOD, GPx) and the expression of maladaptive repair-related genes (Vcam1, Irf8, etc.). Pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) were significantly elevated in KO mice. We found increased oxidative and inflammatory markers in CKD patients' serum and urine, highlighting the role of OS in disease progression. Treatment with 6K, a Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 protein-protein interaction (PPI) inhibitor, markedly improved renal function, suppressed OS and ferroptosis, and upregulated adaptive repair-related genes and downregulated maladaptive repair-related genes in bIRI mice. Compound 6K exhibited a kidney-targeted distribution profile, with an area under the concentration-time curve (AUC) kidney/AUC blood ratio of 1.01, suggesting its potential for targeted treatment of kidney diseases. In human kidney-2 (HK-2) cells, 6K activated the Nrf2-GPX4 axis, thereby alleviated RSL3-induced suppression of GPX4 expression, reduced reactive oxygen species (ROS) accumulation and lipid peroxidation, and mitigated ferroptosis. Furthermore, 6K treatment significantly delayed fibrosis progression in bIRI and unilateral ureteral obstruction (UUO) models. In summary, our findings demonstrate that Nrf2 deficiency exacerbates AKI-CKD progression through redox imbalance and ferroptosis-mediated maladaptive repair. Targeting Keap1-Nrf2 with 6K protects against renal injury and fibrosis, highlighting its therapeutic potential for kidney diseases.