The G1 and G2 variants of the APOL1 gene increase the risk of chronic kidney disease (CKD) in individuals of African descent. In the presence of secondary stressors such as inflammation and hypoxia, these gain-of-function variants can induce podocyte dysfunction and cell death through mechanisms that are not fully understood. To identify genes that influence the cytotoxic effects of APOL1 variants under hypoxic conditions, we conducted a comprehensive whole-genome RNA interference (RNAi) screen. We found that silencing several peroxisomal (PEX) genes significantly intensified the cytotoxicity associated with the G1 and G2 variants, revealing the previously unknown role of peroxisomes in APOL1-related cytotoxicity. Importantly, enhancing peroxisomal function through both genetic and pharmacological approaches led to a significant reduction in cytotoxicity linked to these variants. We also identified a peroxisomal targeting signal at the C-terminus of APOL1 that facilitates its translocation to peroxisomes during hypoxia, and mutations in this signal were found to reduce the cytotoxic effects of the variants. Collectively, our findings underscore the importance of peroxisomal function in the pathogenesis of CKD associated with APOL1 variants and suggest that targeting peroxisomes may represent an effective therapeutic strategy to mitigate CKD risk in vulnerable populations.

TRANSLATIONAL STATEMENT Peroxisomal function is necessary to protect from APOL1 (kidney risk variant) KRV-mediated cytotoxicity in the presence of hypoxia, and targeting peroxisomes may represent an effective therapeutic strategy to mitigate CKD risk.

The authors have declared no competing interest.

This study was funded by funds from The Ohio State University (OSU) Department of Internal Medicine and National Institutes of Health grants R01DK132230 (NSP), and K08DK123411 (SMM).

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Ethics committee/IRB of The Ohio State University gave ethical approval for this work

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