The Berberine Derivative BBR684 Inhibits VDAC Oligomerization to Suppress Ferroptosis in Acute Kidney Injury.

BACKGROUND: Ferroptosis is an iron-dependent form of programmed cell death driven by lipid peroxidation and is implicated in acute kidney injury (AKI). OBJECTIVE: Here, we investigated the therapeutic potential of BBR684, a derivative of berberine, in suppressing ferroptosis and alleviating AKI. METHODS: The anti-ferroptotic activity in HK-2 cells was assessed by Western blot, flow cytometry, and immunofluorescence. Renal fibrosis and the expression of related proteins were evaluated using Masson staining, PI staining, and immunohistochemistry. RESULTS: Our findings suggest that BBR684 exhibits superior efficacy compared to berberine in reversing erastin-induced ferroptosis in HK-2 cells. Mechanistically, BBR684 confers cytoprotection by restoring glutathione (GSH) levels and glutathione peroxidase 4 (GPX4) expression, thereby reducing oxidative stress. Moreover, BBR684 directly binds to the voltage-dependent anion channel (VDAC), inhibiting its oligomerization and transport activity. This interaction reduces intracellular reactive oxygen species (ROS) and calcium (Ca2+) accumulation, preserves mitochondrial integrity, and ultimately inhibits ferroptosis. In vivo, BBR684 significantly alleviated folic acid (FA)-induced acute kidney injury (AKI) in mice, as evidenced by decreased serum creatinine and blood urea nitrogen levels, along with improved renal histopathology. Additionally, BBR684 diminishes inflammatory responses and lipid peroxidation, reinforcing its renoprotective effects. Collectively, these results identify BBR684 as a potent ferroptosis inhibitor with therapeutic potential for AKI and other ferroptosis-related diseases. CONCLUSIONS: BBR684 inhibits VDAC oligomerization to suppress ferroptosis in acute kidney injury.