BCAT1 Human

What is BCAT1 and what is its primary function in human cells?

BCAT1 (Branched-Chain Aminotransferase 1) is a cytosolic enzyme that initiates the catabolism of branched-chain amino acids (BCAAs) such as leucine, isoleucine, and valine. It catalyzes the transfer of amino groups from BCAAs to α-ketoglutarate, forming glutamate and the corresponding branched-chain α-keto acids (BCKAs). This conversion represents the first step in BCAA metabolism, providing essential precursors for macromolecular synthesis and energy production. RNA sequencing data has confirmed that BCAT1 is the most abundantly expressed BCAT isoform in human monocyte-derived macrophages, suggesting its dominant role in BCAA metabolism in these cells . The enzyme plays a critical role in metabolic reprogramming during immune cell activation, particularly in macrophages and T cells, where it influences inflammatory responses and cellular metabolism.

How does BCAT1 differ from BCAT2 in terms of cellular localization and function?

The primary differences between BCAT1 and BCAT2 involve their cellular localization, tissue distribution, and functional roles:

• BCAT1 (cytosolic isoform): Predominantly localized in the cytoplasm of cells, BCAT1 is particularly abundant in macrophages, activated T cells, and various cancer cells. In human monocyte-derived macrophages, BCAT1 mRNA levels are markedly increased compared to BCAT2, making it the major source of BCAA catabolism in these cells .

• BCAT2 (mitochondrial isoform): Localized in the mitochondria and more widely expressed across different tissues, particularly in metabolically active organs.

This distinct localization creates different metabolic consequences: BCAT1-mediated BCAA catabolism in the cytosol directly influences cytosolic signaling pathways, while BCAT2 activity is more integrated with mitochondrial energy production. In breast cancer, BCAT1 expression is significantly associated with HER2+ and luminal B subtypes, while BCAT2 expression correlates with the luminal A subtype, suggesting distinct roles in cancer biology .

When investigating isoform-specific functions, researchers typically employ selective inhibitors like ERG240, which inhibits BCAT1 with an IC50 of 0.1-1 nM without affecting BCAT2 activity .

What techniques are used to measure BCAT1 expression and activity in human samples?

Researchers employ several complementary techniques to accurately measure BCAT1 expression and activity:

For expression analysis:

• qRT-PCR: Quantifies BCAT1 mRNA levels using specific primers and systems like the Viaa 7 Real-Time PCR system mentioned in the research

• Western blotting: Detects BCAT1 protein using specific antibodies, often visualized with chemiluminescent substrates like SuperSignal West Femto

• Immunohistochemistry: For tissue localization and expression pattern analysis

• RNA sequencing: Provides comprehensive transcriptomic profiling and relative expression compared to other genes

For activity measurement:

• Continuous fluorometric assays: These can directly measure BCAT1 aminotransferase activity in vitro

• Metabolite analysis by GC/MS or LC/MS: Measures levels of BCAAs, BCKAs, and downstream metabolites like citrate

• Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR): Assesses broader metabolic effects of BCAT1 activity using technologies like Seahorse analyzers

• RNAi approaches: siRNA-mediated knockdown of BCAT1 helps confirm the specificity of observed metabolic effects

These techniques collectively provide a comprehensive understanding of BCAT1 expression patterns and functional activity in human samples.

How does BCAT1 regulate macrophage metabolic reprogramming during inflammation?

BCAT1 plays a critical role in macrophage metabolic reprogramming during inflammation through several interconnected mechanisms:

• TCA cycle modulation: In LPS-activated macrophages, BCAT1 activity influences the metabolic breakpoint in the TCA cycle. BCAT1 inhibition leads to increased citrate accumulation, suggesting BCAT1 affects the flux from citrate to downstream metabolites .

• IRG1/itaconate axis regulation: One of the most significant findings is that BCAT1 inhibition with ERG240 dramatically reduces IRG1 levels and itaconate production . Itaconate is a key immunomodulatory metabolite that can inhibit succinate dehydrogenase (SDH) and bacterial growth while also modulating inflammatory responses.

• Bioenergetic reprogramming: BCAT1 inhibition decreases both oxygen consumption (OCR) and glycolysis (ECAR) in LPS-stimulated human monocyte-derived macrophages, affecting:

  • Basal respiration

  • Estimated ATP production

  • Maximal respiration

  • Glycolysis and glycolytic capacity

• Inflammatory response modulation: ERG240 treatment results in a less proinflammatory transcriptomic signature in macrophages, suggesting BCAT1 as a regulator of inflammatory gene expression .

These findings establish BCAT1 as a central regulator of metabolic rewiring during macrophage activation, with significant implications for inflammatory responses and potential therapeutic targeting.

What are the key metabolic pathways influenced by BCAT1 activity?

BCAT1 activity influences several interconnected metabolic pathways that collectively impact cellular function:

• BCAA metabolism: By catalyzing the first step in BCAA catabolism, BCAT1 controls the conversion of BCAAs to their corresponding α-keto acids, which can then feed into other metabolic pathways.

• TCA cycle: Research shows BCAT1 activity affects the TCA cycle, particularly at the citrate/isocitrate point. In activated macrophages, BCAT1 inhibition results in increased citrate levels, suggesting that BCAT1 influences the metabolic breakpoint in the TCA cycle .

• Itaconate synthesis pathway: BCAT1 inhibition leads to reduced IRG1 levels and itaconate synthesis in macrophages . Itaconate is a bactericidal metabolite produced through the IRG1 pathway that also has immunomodulatory functions.

• Glycolysis: BCAT1 inhibition reduces glycolytic capacity in activated macrophages, indicating significant crosstalk between BCAA metabolism and glycolysis .

• Cellular respiration: Oxygen consumption rate (OCR) measurements show that BCAT1 inhibition decreases basal respiration, estimated ATP production, and maximal respiration .

• In T cells, BCAT1-mediated cytosolic leucine catabolism generates β-hydroxy β-methylbutyric acid (HMB), which regulates the mTORC1-HIF1α pathway important for IL-17 production .

• Fatty acid metabolism: BCAT1 may regulate fatty acid production, as its expression in adipose tissue correlates with weight regain .

These metabolic connections highlight BCAT1's central role as a metabolic hub coordinating energy production, inflammatory mediator synthesis, and cellular signaling.

How does BCAT1-mediated leucine metabolism affect T cell function and differentiation?

BCAT1-mediated leucine metabolism plays a crucial role in T cell function and differentiation, particularly in Th17 responses:

• TCR activation increases expression: T-cell receptor (TCR) stimulation upregulates both BCAT1 expression and SLC7A5 (a major BCAA transporter) in human CD4+ T cells, facilitating increased leucine influx and catabolism .

• Alternative cytosolic leucine catabolism: Activated CD4+ T cells utilize an alternative pathway of cytosolic leucine catabolism involving BCAT1 and 4-hydroxyphenylpyruvate dioxygenase (HPD)/HPD-like protein (HPDL) to generate β-hydroxy β-methylbutyric acid (HMB) .

• IL-17 production regulation: Inhibition of BCAT1-mediated cytosolic leucine metabolism, either with BCAT1 inhibitor 2 (Bi2) or through silencing of BCAT1, HPD, or HPDL using shRNA, attenuates IL-17 production. Importantly, HMB supplementation abrogates this effect, confirming its role in IL-17 regulation .

• mTORC1-HIF1α pathway modulation: Mechanistically, HMB contributes to the regulation of the mTORC1-HIF1α pathway, a major signaling pathway for IL-17 production, by increasing the mRNA expression of HIF1α .

• Therapeutic implications: In an experimental autoimmune encephalomyelitis (EAE) model, blockade of BCAT1-mediated leucine catabolism mitigated disease severity by decreasing HIF1α expression and IL-17 production in spinal cord mononuclear cells .

These findings establish BCAT1-mediated leucine metabolism as a critical regulator of T cell differentiation and inflammatory responses, with potential implications for autoimmune disease treatment.

What validated inhibitors of BCAT1 exist and how do they affect cellular metabolism?

Several BCAT1 inhibitors have been validated and characterized for their effects on cellular metabolism:

• ERG240: A water-soluble structural analogue of leucine that selectively inhibits BCAT1 with an IC50 of 0.1-1 nM, with no observed inhibition of BCAT2 . In LPS-stimulated macrophages, ERG240 treatment results in:

  • Decreased oxygen consumption rate (OCR) and extracellular acidification rate (ECAR)

  • Reduced IRG1 expression and itaconate synthesis

  • Increased citrate accumulation

  • Altered inflammatory gene expression

• BCAT1 inhibitor 2 (Bi2): Used to attenuate IL-17 production in T cells by targeting BCAT1-mediated leucine metabolism .

• L-β-homoleucine (LβhL): A leucine analog and competitive inhibitor of BCAT1 that decreases IL-17 production by TCR-activated CD4+ T cells and reduces severity in experimental autoimmune encephalomyelitis models .

These inhibitors demonstrate that pharmacological targeting of BCAT1 can effectively modulate cellular metabolism and inflammatory responses. When studying these inhibitors, researchers typically examine both direct effects on BCAA metabolism and broader metabolic impacts on pathways like glycolysis and mitochondrial respiration using technologies such as Seahorse analyzers, GC/MS for metabolite quantification, and protein expression analysis .

How does BCAT1 inhibition affect inflammatory disease models?

BCAT1 inhibition shows promising therapeutic effects in multiple inflammatory disease models:

• Rheumatoid arthritis model: Oral administration of ERG240 reduces the severity of collagen-induced arthritis in mice, in part by decreasing macrophage infiltration . This suggests potential application in autoimmune joint diseases.

• Crescentic glomerulonephritis model: ERG240 treatment reduces inflammation in a rat model of kidney inflammation characterized by macrophage infiltration . The WKY rat strain used in this model shows a genetically determined Hif-1α-mediated glycolytic transcriptome signature in macrophages, which may explain their susceptibility to glomerular inflammation and the efficacy of BCAT1 inhibition .

• Experimental autoimmune encephalomyelitis (EAE): Blockade of BCAT1-mediated leucine catabolism, either through BCAT1 inhibitor or LβhL treatment, mitigates EAE severity by decreasing HIF1α expression and IL-17 production in spinal cord mononuclear cells . This demonstrates efficacy in a model of multiple sclerosis.

The protective effects of BCAT1 inhibition in these diverse inflammatory models suggest that BCAT1 may have a regulatory role in macrophages and T cells activated by different proinflammatory stimuli, beyond just LPS stimulation. This is consistent with the observation that ERG240 inhibits Irg1 mRNA levels in TNF-activated human MDMs as well .

These findings collectively establish BCAT1 as a druggable target for controlling inflammation in multiple disease contexts characterized by immune cell infiltration and activation.

What challenges exist in targeting BCAT1 for therapeutic purposes?

Targeting BCAT1 for therapeutic purposes presents several challenges that researchers must address:

• Selectivity and specificity:

  • Designing inhibitors that selectively target BCAT1 without affecting BCAT2 or other aminotransferases

  • While ERG240 shows selectivity for BCAT1 over BCAT2 , maintaining such selectivity with drug-like molecules that have favorable pharmacokinetic properties remains challenging

  • Understanding and avoiding off-target effects on other metabolic enzymes

• Tissue-specific delivery:

  • Delivering BCAT1 inhibitors specifically to inflammatory macrophages or T cells

  • Avoiding effects on BCAT1 in non-target tissues where it may have important physiological functions

  • Developing targeted delivery systems for cell type-specific inhibition

• Context-dependent effects:

  • BCAT1 inhibition may have different effects depending on the inflammatory context

  • Itaconate, which is reduced by BCAT1 inhibition, has context-dependent roles (antimicrobial, anti-inflammatory in some settings)

  • Determining which inflammatory conditions would benefit most from BCAT1 inhibition

• Balancing immune modulation:

  • Ensuring that BCAT1 inhibition reduces harmful inflammation without compromising essential immune responses

  • Determining appropriate dosing regimens that achieve therapeutic benefits without excessive immunosuppression

• Translation from animal models:

  • While BCAT1 inhibition shows promise in mouse models of arthritis, rat models of glomerulonephritis , and mouse models of experimental autoimmune encephalomyelitis , human metabolism and inflammation may differ

  • Clinical studies would need to carefully assess both efficacy and safety in humans

Despite these challenges, the fact that BCAT1 gene knockout mouse experiments are feasible suggests that targeted BCAT1 inhibition remains a promising therapeutic strategy, particularly for conditions characterized by macrophage or T cell activation .

How does BCAT1 overexpression contribute to cancer progression?

BCAT1 overexpression contributes to cancer progression through multiple mechanisms:

How is BCAT1 expression regulated in different cancer types?

BCAT1 expression is regulated through multiple mechanisms in different cancer types:

• Transcriptional regulation:

  • c-Myc activation: Research shows correlation between c-Myc and BCAT1 expression, creating a potential positive feedback loop in cancer cells

  • Wnt signaling pathway: BCAT1 appears to both respond to and influence Wnt pathway activation in lung cancer

  • Cancer-specific transcription factors may drive BCAT1 expression in different tumor types

• Cancer subtype-specific regulation:

  • In breast cancer, BCAT1 expression is significantly associated with HER2+ and luminal B subtypes

  • BCAT2 expression is associated with the luminal A subtype

  • This differential expression pattern suggests distinct regulatory mechanisms across cancer subtypes

• Metabolic regulation:

  • Cancer cells with altered metabolism may upregulate BCAT1 to support their metabolic needs

  • Nutrient availability and cellular energy status may influence BCAT1 expression

• Genetic and epigenetic alterations:

  • Copy number alterations affecting the BCAT1 gene locus

  • Epigenetic modifications including DNA methylation and histone modifications

• Clinical correlations:

  • BCAT1 upregulation correlates with nodal metastasis and advanced stages in NSCLC

  • BCAT1 serves as an independent predictor of triple-negative breast cancer prognosis

  • These correlations suggest that BCAT1 expression increases during cancer progression

Research has demonstrated that a large number of studies show increased BCAT1 expression accompanied by increased c-Myc, cyclin D1, and MMP7 expression, indicating coordinated regulation of these genes in cancer contexts . Understanding these regulatory mechanisms is crucial for developing targeted approaches to modulate BCAT1 expression in cancer.

Can BCAT1 serve as a biomarker or therapeutic target in specific cancer types?

BCAT1 shows significant potential as both a biomarker and therapeutic target in specific cancer types:

As a biomarker:

As a therapeutic target:

• Direct inhibition approaches:

  • While BCAT1-specific inhibitors like ERG240 have been developed for research purposes , their adaptation for cancer therapy is still evolving

  • Selective targeting of BCAT1 could potentially disrupt cancer metabolism with minimal effects on normal cells

• Targeting downstream pathways:

  • Inhibiting Wnt/Myc signaling in BCAT1-overexpressing cancers

  • Combination approaches targeting both BCAT1 and its downstream effectors

• Experimental validation:

  • BCAT1 gene knockout mouse experiments are feasible, suggesting that targeted therapy approaches may be viable

  • RNA interference approaches have demonstrated that BCAT1 silencing can reduce cancer cell proliferation and invasion

What molecular mechanisms link BCAT1 to the IRG1/itaconate axis in macrophages?

The molecular mechanisms linking BCAT1 to the IRG1/itaconate axis in macrophages involve complex metabolic and signaling pathways:

• TCA cycle rewiring:

  • BCAT1 inhibition with ERG240 leads to increased citrate levels in LPS-stimulated macrophages

  • This suggests BCAT1 activity influences the metabolic breakpoint in the TCA cycle at the isocitrate dehydrogenase 1 (IDH1) level

  • The recently discovered discontinuity in the TCA cycle at IDH1 results in flux redirection towards citrate/aconitate, enabling large production of fatty acids and itaconate

  • BCAT1 appears to regulate this metabolic axis, particularly affecting the availability of substrate for IRG1-mediated itaconate production

• Transcriptional regulation of IRG1:

  • BCAT1 inhibition dramatically reduces IRG1 mRNA and protein levels

  • This suggests BCAT1 activity influences the transcriptional regulation of IRG1, possibly through metabolite-sensitive transcription factors

  • Both pharmacological inhibition with ERG240 and siRNA-mediated knockdown of BCAT1 consistently reduce IRG1 protein levels in human macrophages

• Energy metabolism coupling:

  • BCAT1 inhibition reduces both oxygen consumption and glycolysis in activated macrophages

  • This metabolic reprogramming may indirectly affect IRG1 expression and itaconate synthesis through altered cellular energy status

• In vivo confirmation:

  • Peritoneal macrophages from mice injected with LPS and ERG240 show reduced levels of Irg1/itaconate together with a diminished proinflammatory transcriptome compared to mice injected with LPS alone

  • This provides in vivo evidence for the regulatory connection between BCAT1 and the IRG1/itaconate axis

These mechanisms establish BCAT1 as a regulator of IRG1-dependent macrophage activation, with important implications for inflammatory responses and potential therapeutic targeting in inflammatory diseases.

How do researchers distinguish between BCAT1-specific effects and broader BCAA metabolism alterations?

Distinguishing BCAT1-specific effects from broader BCAA metabolism alterations requires sophisticated experimental design:

• Use of selective inhibitors:

  • ERG240 selectively inhibits BCAT1 (IC50 of 0.1-1 nM) without affecting BCAT2

  • Other selective inhibitors like BCAT1 inhibitor 2 (Bi2) and L-β-homoleucine (LβhL) provide additional tools to confirm BCAT1-specific effects

  • Comparing effects across multiple selective inhibitors helps identify consistent BCAT1-specific phenotypes

• Genetic manipulation approaches:

  • siRNA-mediated knockdown of BCAT1: The search results describe using siGENOME SMARTpool for human BCAT1 to specifically reduce BCAT1 expression

  • Comparative knockdown of BCAT1 vs. BCAT2 helps distinguish isoform-specific effects

  • The research demonstrates that siRNA-mediated inhibition of BCAT1 mRNA levels results in decreased OCR and ECAR levels, phenocopying the effects of ERG240

• Downstream metabolite rescue experiments:

  • Supplement with specific BCAA metabolites to determine which can rescue BCAT1 inhibition phenotypes

  • HMB supplementation abrogates the effect of BCAT1 inhibition on IL-17 production in T cells

  • This approach identifies which metabolic products of BCAT1 are responsible for specific cellular effects

• System-specific readouts:

  • In macrophages, measure IRG1/itaconate levels as a specific readout of BCAT1 function

  • In T cells, assess IL-17 production and mTORC1-HIF1α pathway activation

  • In cancer cells, evaluate effects on Wnt/Myc signaling and proliferation markers

What experimental models are most suitable for studying BCAT1 function?

Researchers utilize a diverse array of experimental models to study BCAT1 function across different biological contexts:

In vitro models:

• Primary human monocyte-derived macrophages (hMDMs): These cells express high levels of BCAT1 and are suitable for studying its role in immune cell metabolism and inflammation

• Primary human CD4+ T cells: Used to study BCAT1's role in T cell activation and differentiation, particularly in Th17 responses

• Cancer cell lines:

  • H1299 and other lung cancer cell lines: Used to study BCAT1's role in cancer proliferation and invasion

  • BEAS-2B: Normal bronchial epithelial cell line used as a comparative control

• Genetic manipulation systems:

  • siRNA knockdown: Using siGENOME SMARTpool for human BCAT1 (100 nM) with Dharmafect 1 transfection reagent

  • shRNA approaches: For stable knockdown of BCAT1, HPD, or HPDL

In vivo models:

• Collagen-induced arthritis mouse model: Used to study the anti-inflammatory effects of ERG240 in joint inflammation

• Crescentic glomerulonephritis rat model (WKY strain): Used to evaluate BCAT1 inhibition in kidney inflammation characterized by macrophage infiltration

• Experimental autoimmune encephalomyelitis (EAE) model: Used to study the effects of BCAT1 inhibition on IL-17 production and disease severity in a multiple sclerosis model

For metabolic and functional analyses:

• Extracellular flux analysis (Seahorse technology): Measures oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) to assess mitochondrial respiration and glycolysis

• Metabolite profiling: GC/MS analysis for metabolites like citrate

• Protein expression analysis: Western blotting for BCAT1, IRG1, and other relevant proteins

• Transcriptome analysis: RNA-sequencing and qRT-PCR for gene expression changes

The complementary use of these diverse models allows researchers to comprehensively investigate BCAT1 function from molecular mechanisms to physiological relevance in disease settings.

What are the key unresolved questions about BCAT1 function in human biology?

Despite significant advances in understanding BCAT1, several key questions remain unresolved:

• Regulatory mechanisms: How is BCAT1 expression and activity regulated in different cell types and disease states? What transcription factors, signaling pathways, and post-translational modifications control BCAT1 function?

• Cell type-specific roles: While BCAT1's functions in macrophages and T cells are being elucidated, its roles in other immune cells, neurons, and tissue-specific cells remain largely unexplored.

• Metabolite signaling: How do BCAT1-dependent metabolites (like HMB) function as signaling molecules to regulate gene expression and cellular processes? What are the molecular mechanisms by which these metabolites influence pathways like mTORC1-HIF1α?

• Integrated metabolism: How does BCAT1-mediated BCAA metabolism integrate with other metabolic pathways in different physiological and pathological contexts? The complex interplay between BCAA metabolism, the TCA cycle, glycolysis, and lipid metabolism requires further investigation.

• Therapeutic targeting: What are the optimal approaches for targeting BCAT1 in specific diseases? Can tissue-specific or cell type-specific delivery methods be developed? What combination therapies might enhance the efficacy of BCAT1 inhibition?

• Genetic variation: How do genetic variants in BCAT1 affect enzyme function and disease susceptibility? Are there population-specific differences in BCAT1 function or regulation?

• Developmental roles: What are BCAT1's functions during development and cellular differentiation? Does it play critical roles in stem cell biology or tissue regeneration?

Addressing these questions will require innovative approaches and technologies, from single-cell analyses to tissue-specific genetic models and advanced metabolomics.

How might future BCAT1-targeted therapeutics be developed and applied?

Future BCAT1-targeted therapeutics could follow several promising development paths:

• Enhanced selective inhibitors:

  • Building on the success of ERG240, Bi2, and LβhL to develop inhibitors with improved pharmacokinetic properties

  • Structure-based drug design utilizing crystallographic data on BCAT1

  • Development of allosteric inhibitors that may offer greater selectivity

• Disease-specific applications:

  • Inflammatory conditions: Expanding beyond arthritis and glomerulonephritis to other macrophage-driven inflammatory diseases

  • Autoimmune diseases: Building on the success in experimental autoimmune encephalomyelitis to target Th17-driven conditions like psoriasis or inflammatory bowel disease

  • Cancer therapy: Developing BCAT1 inhibitors for specific cancer subtypes where BCAT1 serves as a driver, such as HER2+ breast cancer or non-small cell lung cancer

• Targeted delivery approaches:

  • Macrophage-targeted nanoparticles containing BCAT1 inhibitors

  • T cell-directed delivery systems

  • Tumor-targeted approaches for cancer applications

• Combination therapies:

  • Combining BCAT1 inhibition with existing anti-inflammatory agents

  • Pairing with cancer therapeutics that target complementary pathways

  • Metabolic combination approaches that simultaneously target multiple metabolic vulnerabilities

• Biomarker-guided therapy:

  • Using BCAT1 expression or activity as a biomarker to identify patients most likely to respond to BCAT1-targeted therapy

  • Developing companion diagnostics for BCAT1-targeted drugs

• Novel formulations:

  • Oral formulations for chronic treatment of inflammatory conditions

  • Injectable formulations for acute interventions

  • Extended-release preparations for sustained inhibition

The development of these therapeutic approaches will benefit from the growing understanding of BCAT1's role in different biological contexts and the promising results already observed in preclinical models of inflammatory diseases and cancer.

How does BCAT1 research contribute to our broader understanding of metabolism in health and disease?

BCAT1 research provides valuable insights into our broader understanding of metabolism in health and disease:

• Metabolic-immune interface: BCAT1 research reveals how metabolic enzymes can directly influence immune cell function and inflammatory responses. The connection between BCAT1, the TCA cycle, and the IRG1/itaconate axis demonstrates how metabolic rewiring shapes immune cell function .

• Cell type-specific metabolism: The predominant expression of BCAT1 in macrophages and its upregulation in T cells upon activation highlights the importance of cell type-specific metabolic programs . This helps us understand how different cells adapt their metabolism to support specialized functions.

• Metabolic basis of disease: BCAT1 overexpression in cancer and its role in inflammatory conditions illustrate how altered metabolism can drive disease pathogenesis . This supports the emerging view that metabolic rewiring is not merely a consequence but often a driver of disease.

• Metabolite signaling: The discovery that BCAT1-dependent metabolites like HMB can regulate signaling pathways like mTORC1-HIF1α demonstrates the importance of metabolites as signaling molecules . This expands our understanding beyond their traditional roles as energy intermediates.

• Therapeutic targeting of metabolism: Success in targeting BCAT1 in preclinical models of inflammatory diseases and cancer provides proof-of-concept for metabolic enzymes as therapeutic targets . This encourages exploration of other metabolic nodes for intervention.

• Integrated metabolism: BCAT1 research reveals complex interactions between BCAA metabolism, the TCA cycle, glycolysis, and inflammatory pathways . This integrated view challenges simplified linear models of metabolism and emphasizes the importance of metabolic networks.