Fibrolamellar carcinoma (FLC) is a rare but devastating early-onset liver cancer that affects mainly adolescents and young adults. FLC is chemo- and radio-resistant, and there are no known risk factors or biomarkers. There is currently no standard of care, and even surgical resection is not available for most of the affected population. Additionally, there is a high rate of recurrence after surgery. Therefore, there is a dire need for effective therapeutics. The primary molecular driver of FLC is the fusion oncoprotein, DNAJ-PKAc (DP), which is the result of a ~400kb heterozygous deletion on chromosome 19 and subsequent in-frame fusion of parts of two genes, DNAJB1 (DnaJ Heat Shock Protein Family Member B1) and PRKACA (Protein Kinase CAMP-Activated Catalytic subunit Alpha). Two landmark mouse studies demonstrated that DP is sufficient to drive tumorigenesis, and DP has been detected in the vast majority of patient tumor samples that have been sequenced to-date. DP remains challenging to target therapeutically. It is critical, therefore, to expand our understanding of the FLC molecular landscape to identify druggable pathways/targets. In the past, various techniques within the transcriptomic space were utilized on patient tissue to understand how gene regulatory networks are altered in FLC. Phospho-proteomics has been applied, but it has been primarily in cell models of FLC. There has been very little investigation of metabolic rewiring in FLC. My recent study published in Cell Reports Medicine (2024) is one of the first to advance this area of investigation. My work, which also includes functional validation in various disease models of FLC, points to potential new therapeutic avenues. Specifically, I was the first to perform the most comprehensive integrative analysis of proteomics and metabolomics data generated from human tumor samples that resulted in a robust metabolic model for FLC. I also led a collaborative effort to functionally validate critical aspects of the model via: (1) mitochondrial respirometry analyses in frozen patient tissue and primary cell lines, (2) RNAi- and small molecule inhibitor (SMI)-mediated loss of function (LOF) assays in fresh FLC tumor tissue slices from patients, and (3) nutrient manipulation and SMI-mediated LOF assays in primary cell lines. Through this work I have proposed a model of cellular energetics in FLC with several novel and intriguing features. First, the results implicate a partial decoupling of glycolysis from pyruvate production. Functional studies confirmed lack of dependence on glycolysis in FLC. Moreover, SDS (serine dehydratase) was identified as a critical enzyme for FLC cell viability, likely due to pyruvate production from serine. Second, our model strongly suggests heavy mitochondrial consumption of pyruvate. We demonstrated in patient tissue slices that FLC cell survival is highly dependent on VDAC (voltage dependent anion channel), a mitochondrial gatekeeper for anions including pyruvate. In fact, the compound that alters VDAC activity affects FLC survival more dramatically than ~400 other compounds that were tested by a collaborator in a high throughput screen. Third, my model points to highly rewired metabolic processes in the mitochondria in FLC, most notably proline anabolism mediated by OAT (ornithine aminotransferase) hyperactivity and OTC (ornithine transcarbamylase) hypoactivity, with glutamine-derived glutamate at least partially fueling the process. Functional assays in a FLC primary cell line showed that GLS (glutaminase; converts glutamine to glutamate) is crucial for FLC cell survival. This exciting finding partially motivated an ongoing clinical trial (run by collaborators at Johns Hopkins School of Medicine who generated data supporting our findings in a mouse model of FLC) targeting glutamine metabolism in FLC patients. The proceeding discourse centers the metabolic landscape of FLC as a rich source of untapped therapeutic potential.