Nephrolithiasis is highly prevalent and associated with the increased risk of kidney cancer. The tumor suppressor von Hippel-Lindau (VHL) is critical for renal cancer development, however, its role in kidney stone disease has not been fully elucidated until now. Here we reported VHL expression was upregulated in renal epithelial cells upon exposure to crystal. Utilizing Vhl+/mu mouse model, depletion of VHL exacerbated kidney inflammatory injury during nephrolithiasis. Conversely, overexpression of VHL limited crystal-induced lipid peroxidation and ferroptosis in a BICD2-depdendent manner. Mechanistically, VHL interacted with the cargo adaptor BICD2 and promoted itsd K48-linked poly-ubiquitination, consequently resulting in the proteasomal degradation of BICD2. Through promoting STAT1 nuclear translocation, BICD2 facilitated IFNγ signaling transduction and enhanced IFNγ-mediated suppression of cystine/glutamate antiporter system Xc-, eventually increasing cell sensitivity to ferroptosis. Moreover, we found that the BRAF inhibitor impaired the association of VHL with BICD2 through triggering BICD2 phosphorylation, ultimately causing severe ferroptosis and nephrotoxicity. Collectively, our results uncover the important role of VHL/BICD2/STAT1 axis in crystal kidney injury and provide a potential therapeutic target for treatment and prevention of renal inflammation and drug-induced nephrotoxicity.© 2023. The Author(s).