Clear cell renal cancer metabolism: Secrets behind fatty acid synthesis.

e16500 Background: Clear renal cell carcinoma (KIRC) is the most common histological subtype of renal cell carcinoma, known for its clear appearance due to accumulation of lipids and glycogen.This study investigates the genetic expression of key enzymes involved in fatty acid synthesis and breakdown, focusing on the cause of lipid storage and the cell’s purpose behind it. We examine the expression of enzymes involved in the rate-limiting steps of fatty acid metabolism, including acetyl-CoA carboxylase Alpha (ACACA), which catalyzes the cytoplasmic conversion of acetyl-CoA to malonyl-CoA, initiating fatty acid synthesis; acetyl-CoA carboxylase Beta (ACACB), the mitochondrial isoform of the enzyme ; and Carnitine palmitoyltransferase 1A (CPT1A), which catalyzes the rate-limiting step in fatty acid β-oxidation. Additionally, the study investigates ATP citrate lyase (ACLY), the enzyme that catalyzes the degradation of citrate to acetyl-CoA, impacting fatty acid metabolism. Methods: The Cancer Genome Atlas (TCGA), Tumor Immune Estimation Resource (TIMER 2.0), Gene Expression Profiling Interactive Analysis (GEPIA 2.0), and the University of Alabama at Birmingham Cancer Data Analysis (UALCAN) Portal were utilized to investigate the genetic expression of ACACA, ACACB, CPT1A, and ACLY in KIRC compared to normal tissue. TIMER 2.0 (tumor t = 533, normal n = 72), GEPIA 2.0 (t = 523, n = 100), and UALCAN (t = 533, n = 72) were employed to explore the differential expression of these genes. To further validate the findings, publicly available datasets from the NCBI GEO database, specifically GSE53757 (t = 72, n= 72) and GSE66270 (t = 14, n = 14), were analyzed to detect differential expression ensuring robust and reliable results. Results: ACACA, ACACB, and CPT1A were significantly downregulated across the three databases used: TIMER 2.0, GEPIA 2.0, and UALCAN. This trend was further validated by analyzing NCBI GEO datasets GSE53757 and GSE66270, which confirmed the findings with statistically significant results (adjusted p-values < 0.05 and |Log2FC| > 0.8).As these results do not fully account for the observed microscopic appearance, we investigated ACLY expression using the same databases and datasets. Notably, ACLY was found to be significantly upregulated across all platforms, with highly robust statistical significance (p-value 0.05, adjusted p-value < 1.21e-11, and |Log2FC| > 1.1). Conclusions: In KIRC, fatty acid-related metabolic enzymes are downregulated, but increased glutamine deamination leads to higher citrate availability, which inhibits phosphofructokinase 1. To compensate, KIRC upregulate ACLY degrading citrate and producing actylcoA, reinforcing fatty acid synthesis by mass effect despite the downregulation of related enzymes. Targeting ACLY to disrupt this compensatory mechanism and inhibit glycolysis could offer a promising therapeutic strategy for KIRC treatment.