Cover Story Current Issue

The small intestine, as the primary site of nutrient absorption, integrates signals from dietary components and gut microbiota to coordinate systemic energy balance, metabolism, and glucose homeostasis alongside other tissues such as the pancreas, liver, and brain. Nuclear receptors represent one mechanism by which the intestinal epithelium senses and respond to dietary signals via transcriptional regulation of metabolic programs. The Peroxisome Proliferator Activated Receptors (PPARs), including PPARα, PPARδ, and PPARγ, are lipid-responsive nuclear hormone receptors. PPAR transcriptional activity is highly context-dependent, shaped by the availability and affinity of their lipid ligands and co-regulators as well as by cell and tissue types. Whereas PPARγ and PPARδ are established regulators of glucose homeostasis, acting in white adipose tissue, skeletal muscle, and liver to improve insulin sensitivity, PPARα has been primarily associated with hepatic lipid metabolism, where it promotes fatty acid transport, β-oxidation, and ketogenesis. Due to their roles in lipid metabolism and anti-inflammatory processes, selective PPAR agonists are being actively pursued as therapies in clinical and pre-clinical studies for metabolic diseases. Thus, it is critical to improve our understanding of the context-specific and tissue-specific effects of PPAR signaling.

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Current Issue

Metabolic Targeting of ASAH1 in Combination with Carnosine as a Therapeutic Strategy for TNBC

Patrick Ball, Ashok Mari, Romi Gupta

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype with limited targeted therapies, leading to higher mortality compared with other breast cancer subtypes. In our previous study we identified N-acyl sphingosine amidohydrolase 1 (ASAH1) to be overexpressed in TNBC cells and demonstrated its role in promoting TNBC growth and progression. ASAH1 is a metabolic enzyme that converts ceramide into sphingosine and free fatty acids, thereby creating a favorable environment for tumor growth. To gain a more comprehensive understanding of the metabolic alterations associated with ASAH1 inhibition, we performed a large-scale metabolomic analysis of TNBC cells expressing ASAH1 shRNAs. Our analysis revealed a significant increase in carnosine levels following ASAH1 inhibition. Subsequent studies demonstrated that exogenous treatment of TNBC cells with carnosine inhibited their growth. Moreover, combining carnosine with ASAH1 inhibitors (carmofur or ceranib-2) resulted in potent synergistic inhibition of TNBC growth. Mechanistically, the combined treatment led to a greater reduction in mitochondrial membrane potential, increased mitochondrial superoxide production and further increased apoptosis. Collectively, these results identify a new metabolism-based combination therapeutic strategy for the effective treatment of TNBC.

Articles in Press

Metabolic Targeting of ASAH1 in Combination with Carnosine as a Therapeutic Strategy for TNBC

Patrick Ball, Ashok Mari, Romi Gupta

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype with limited targeted therapies, leading to higher mortality compared with other breast cancer subtypes. In our previous study we identified N-acyl sphingosine amidohydrolase 1 (ASAH1) to be overexpressed in TNBC cells and demonstrated its role in promoting TNBC growth and progression. ASAH1 is a metabolic enzyme that converts ceramide into sphingosine and free fatty acids, thereby creating a favorable environment for tumor growth. To gain a more comprehensive understanding of the metabolic alterations associated with ASAH1 inhibition, we performed a large-scale metabolomic analysis of TNBC cells expressing ASAH1 shRNAs. Our analysis revealed a significant increase in carnosine levels following ASAH1 inhibition. Subsequent studies demonstrated that exogenous treatment of TNBC cells with carnosine inhibited their growth. Moreover, combining carnosine with ASAH1 inhibitors (carmofur or ceranib-2) resulted in potent synergistic inhibition of TNBC growth. Mechanistically, the combined treatment led to a greater reduction in mitochondrial membrane potential, increased mitochondrial superoxide production and further increased apoptosis. Collectively, these results identify a new metabolism-based combination therapeutic strategy for the effective treatment of TNBC.

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