Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant hereditary cancersyndrome caused by a germline inactivating mutation in one of the alleles of the gene encoding thetricarboxylic acid (TCA) cycle enzyme fumarate hydratase (FH). HLRCC patients are predisposed to developaggressive papillary renal cell carcinoma type 2 (PRCC2) at an early age. The cancer tissues exhibit a loss-of-heterozygosity at the FH locus indicating biallelic FH inactivation (FH-/-) as a critical event in tumorigenesis.These tumors often metastasize early limiting the effectiveness of surgical intervention. Moreover the tumorsare resistant to all known chemo targeted and radio therapies making PRCC2 a major cause of death amongHLRCC patients. Therefore a treatment strategy against HLRCC is urgently needed.FH-/- imparts very specific changes to the cancer cells. Particularly FH-/- cancer cells accumulate high level ofthe TCA cycle intermediate fumarate which alters cellular signaling in very specific ways. Identifying these FH-/- specific cellular changes will therefore offer ways to target the FH-/- cancer cells while sparing normal cell.This application exploits a FH-/--specific vulnerability that we discovered recently. Specifically FH-/- alterscellular iron signaling making the cells sensitive to an iron dependent cell death mechanism known asferroptosis. We hypothesized that ferritin inhibition in FH-/- cancer cells will further enhance theirsensitivity to ferroptosis while concurrently inhibiting the ferritin-dependent pro-proliferative signaling.We will test our hypothesis through the following aims: (1) Define and compare pathway alterations induced bydifferent methods of ferritin inhibition in FH-/- cancer cells. (2) Evaluate the efficacy of combining ferritininhibition with ferroptosis inducing compounds (FINS) in vitro and confirm their mechanisms of action. (3)Validate the efficacy of combining ferritin inhibition with FINS in vivo. Insights gained from this study willpositively impact the treatment of other ferroptosis sensitive tumors.