FSGS is a major cause of death and reduced quality of life in the military theater and in civilian life. Specifically, two genetic causes of kidney disease can result in FSGS and nephrotic syndrome. Alport’s disease can result in FSGS with progressive disease and APOL1 risk alleles increases risk of collapsing FSGS; both conditions lead to end-stage kidney disease. In both conditions, we hypothesize that CERS6 plays a critical role in these conditions via induction of podocyte apoptosis via overproduction of the cytotoxic C16 ceramide in podocytes. In addition, toxin exposure such as anthracyclines (doxorubicin, adriamycin (ADR)) can also result in FSGS via podocyte toxicity through ceramide production. Our overall hypothesis is that inhibition of CERS6 in podocytes is protective for FSGS in Alport related FSGS, APOL1-associated FSGS, and ADR-induced FSGS. In our proposed studies, we will 1) test and define mechanistically the therapeutic potential of CERS6 in podocyte as a target for control of genetic and toxin related FSGS; 2) identify the metabolic/signaling pathways responsible for these findings via a multi-omics approach; and 3) develop novel CERS6 inhibitors as potential therapeutics for FSGS.