Anaemia in children and adolescents is multifactorial, and evidence on dietary amino-acid intake in relation to anaemia remains limited. This study examined the association between dietary branched-chain amino acid (BCAA) intake and haemoglobin (Hb)-defined anaemia among Chinese children and adolescents using data from the 2016-2019 China Children and Lactating Women Nutrition and Health Survey. Among 11,134 eligible participants aged 6-17 years, quantile g-computation and the Boruta algorithm were first used to screen 20 dietary amino acids. A 1:4 propensity score-matched sample was then constructed, including 455 participants with anaemia and 1,819 with normal Hb levels. Dietary BCAA intake and its components, isoleucine (Ile), leucine (Leu) and valine (Val), were energy-adjusted using the residual method. Machine learning methods were used exploratorily for feature ranking, and conditional logistic regression was used to estimate odds ratios (ORs). After matching, total dietary protein intake was comparable between groups, whereas intakes of total BCAA, Ile, Leu, and Val were significantly lower in the anaemia group. In fully adjusted models, higher intakes of total BCAA, Ile, Leu, and Val were associated with lower odds of Hb-defined anaemia, with ORs of 0.95 (95% CI: 0.92-0.99), 0.82 (95% CI: 0.70-0.95), 0.91 (95% CI: 0.85-0.98) and 0.86 (95% CI: 0.78-0.95), respectively. Supplementary biomarker analyses showed lower ferritin and higher soluble transferrin receptor concentrations in the anaemia group, whereas high-sensitivity C-reactive protein did not differ between groups. These findings suggest that BCAA-related dietary characteristics may provide useful nutritional clues for anaemia-related assessment, although the association should not be interpreted as evidence of a BCAA-specific protective effect.

Triple-negative breast cancer (TNBC) is an aggressive subtype with high metastatic potential and poor prognosis, yet the molecular mechanisms driving metastasis remain incompletely understood. Here, we performed integrated transcriptomic, metabolomic, and imaging mass cytometry (IMC) analyses on tumor tissues from 52 TNBC patients stratified into NonMeta (long-term survival without metastasis, n = 39) and MetaPoor (metastasis-related death within 36 months after metastatic diagnosis, n = 13) groups. Transcriptomic analysis revealed significant enrichment of epithelial-mesenchymal transition (EMT), WNT signaling pathway, and angiogenesis pathways in MetaPoor tumors, with EMT identified as the top enriched hallmark by GSEA. Metabolomic profiling showed decreased branched-chain amino acids (BCAAs) and arginine derivatives, alongside elevated glycerophosphorylcholine (GPC), indicating enhanced metabolic demand and membrane remodeling. IMC-based spatial proteomics identified distinct tumor cell subpopulations, with MetaPoor tumors harboring higher proportions of stem-like and EMT-like cells characterized by upregulated HADHA (BCAA oxidation) and P38, and downregulated ATP5A (oxidative phosphorylation). Multi-omics integration revealed strong correlations between GPC and EMT markers, and between BCAA depletion and HADHA expression. Collectively, our multi-omics study demonstrates that metastatic TNBC is characterized by EMT activation, metabolic reprogramming toward altered BCAA metabolism and oxidative phosphorylation-related protein expression, and remodeling of the tumor immune microenvironment, suggesting candidate molecules that warrant independent validation and further mechanistic investigation.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has become a highly prevalent chronic metabolic disease worldwide. Current clinical drugs are limited by poor long-term efficacy, potential safety risks and high costs. As a popular daily beverage, Gynostemma pentaphyllum exerts prominent hepatoprotective, lipid-regulating and hypoglycemic activities, making it a promising natural agent for MAFLD intervention. In this study, we prepared high-activity secondary gypenosides via snailase-mediated biotransformation, and explored their anti-MAFLD mechanisms through integrated multi-omics analysis and pharmacological validation. The results revealed that snailase efficiently converted primary gypenosides into rare secondary derivatives. Compared with the crude gypenosides from Gynostemma pentaphyllum extract (GYP), the transformed product SGYP exhibited stronger dose-dependent lipid-regulating and anti-inflammatory effects, and effectively alleviated MAFLD-related pathological lesions in mice. Mechanistic investigations demonstrated that SGYP ameliorated high-fat-diet-induced excessive accumulation of branched-chain amino acid (BCAA) in the liver and activated the hepatic AMPK and AKT signaling pathways. Further exogenous BCAA supplementation experiments confirmed that restoring hepatic BCAA homeostasis served as the core mechanism underlying the anti-MAFLD action of SGYP. This study provides an innovative processing technology for the preparation of high-value Gynostemma pentaphyllum products featuring strengthened lipid-lowering, anti-inflammatory activities and prominent hepatoprotective effects.

Nattokinase (NK) is a fibrinolytic enzyme with considerable potential for applications in functional foods and biomedicine; however, its economical and efficient production remains challenging. In this study, tofu-processing wastewater (TPW) was employed as a low-cost nitrogen source for NK production, and integrated transcriptomic and metabolomic analyses were performed to characterize cellular responses and potential regulatory processes under different nitrogen sources. To evaluate the effects of different nitrogen sources on NK production, fermentation was conducted using tryptone (T), soybean peptone (SP), or TPW as the nitrogen source. Both TPW- and SP-based media supported higher NK production than the T-based medium. Transcriptomic analysis showed that the expression of aprN, which encodes nattokinase, was significantly higher under TPW conditions. TPW was characterized by relatively low levels of free amino acids and relatively high abundances of specific oligopeptides and proteins, and these nutritional characteristics were associated with changes in aprN expression and related metabolic responses. Integrated transcriptomic and metabolomic analyses further indicated coordinated changes in nutrient sensing, oligopeptide transport and metabolism, amino acid metabolism, and energy metabolism under TPW conditions. The relatively low levels of branched-chain amino acids (BCAAs) detected in TPW occurred concomitantly with changes in the expression of codY and aprN, suggesting that BCAA-associated nutrient sensing may be associated with the transcriptional regulation of aprN. Meanwhile, changes in the expression of nutrient-responsive genes, including kinA and kinB, suggested that Spo0A-associated regulatory processes may be involved in the cellular response to the nutritional characteristics of TPW. In addition, changes in the expression of several oligopeptide transport-related genes, together with correlations between specific oligopeptides and aprN expression, suggested that oligopeptide transport and metabolism may be associated with NK production under TPW conditions. Genes involved in respiratory-chain and energy metabolism also showed substantial changes in expression, suggesting alterations in cellular energy metabolism that may be associated with NK production. Overall, TPW as an alternative nitrogen source was associated with coordinated changes in nutrient sensing, regulatory processes, and multiple metabolic pathways in B. subtilis, which may collectively contribute to increased NK production. This study provides further insights into the molecular and metabolic responses of B. subtilis to TPW and provides a theoretical basis for TPW valorization, medium optimization, and the economical and efficient production of NK.

Diabetes mellitus substantially increases the risk of cardiovascular, cerebrovascular, renal, retinal and peripheral vascular complications. These are collectively referred to as diabetic panvascular disease. A traditional approach that treats each complication separately is no longer sufficient. An emerging framework places metabolic reprogramming at its center. This review examines how the diabetic environment, including hyperglycemia, insulin resistance, and dyslipidemia, rewires core metabolic pathways in vascular cells. Major changes include the diversion of glucose through the polyol, hexosamine and AGE-PKC axes, lipotoxicity resulting from excessive fatty acids, disruption of amino acid networks such as BCAA and one-carbon metabolism, mitochondrial dysfunction with increased mtROS production, and epigenetic modifications that drive metabolic memory. These interconnected abnormalities promote oxidative stress and chronic inflammation, which in turn lead to endothelial dysfunction, atherosclerosis, microvascular rarefaction, and end-organ damage in the heart, brain, kidney, retina, and peripheral nerves. We also describe the current therapeutic landscape, ranging from established agents such as metformin, SGLT2 inhibitors, GLP-1 receptor agonists, RAAS blockers, and anti-VEGF therapies to emerging mechanism-based strategies including aldose reductase inhibitors, glucokinase activators, PKC, RAGE, NOX, and NLRP3 inhibitors, miRNA modulators, and exosome therapy. Finally, we highlight unmet needs and future directions. These may include multi-omics guided precision phenotyping, cross-organ causal inference, single-cell metabolic flux technologies, and adaptive clinical trial designs. By shifting from a glucose-centric to a metabolic reprogramming-centric paradigm, this review aims to provide a roadmap for developing more targeted therapies for diabetic panvascular disease.

Maintenance of fissed mitochondria is viewed as a defining feature of Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant cancers. However, regulation of this process by accompanying comutations or environmental factors is not clearly defined. Here, by analyzing a subset of pancreatic cancer lesions driven by concurrent Kras[G12D] and GNAS complex locus gene (GNAS[R201C/H]) mutations, we found that despite the presence of mutant Kras, hyperactive Gnas[R201C] maintains mitochondria predominantly in a fused state, which is necessary for tumor growth. Multiplex proteomics, super-resolution microscopy, loss- and gain-of-function studies, coupled with metabolite rescue experiments, revealed that Gnas[R201C]-regulated branched-chain amino acid (BCAA) pathway is a previously unidentified regulator of mitochondrial morphology. Mechanistically, the BCAA pathway, the associated tricarboxylic acid cycle, and aspartate metabolism converge on nicotinamide adenine dinucleotide (NADH-NAD[+]) metabolites to promote mitochondrial elongation. NAD[+] availability is crucial for mitochondrial fusion, as facilitating NAD[+] generation through alternative means promotes fusion. Collectively, we unraveled a new mechanism that drives mitochondrial fusion and showed that the combination of oncogenic signaling and metabolism can maintain distinct mitochondrial morphology within genetic subsets of KRAS-mutant pancreatic cancer.

Methylthioadenosine phosphorylase (MTAP) deficiency is prevalent in pancreatic ductal adenocarcinoma (PDAC). Herein, we reveal that MTAP loss in PDAC induces a branched-chain amino acid (BCAA) dependency by upregulating the expression of BCAA transaminase 1 (BCAT1) through DNA demethylation. We establish that BCAT1 upregulation promotes cell proliferation and migration in PDAC by fueling the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) via BCAA consumption. Moreover, the BCAA dependency contributes to a more aggressive phenotype via activation of cancer-associated pathways. In addition, the BCAT1 inhibitor BAY-069 demonstrates remarkable therapeutic efficacy in MTAP-deficient PDAC by diminishing the BCAA-facilitated OXPHOS. Finally, clinical analysis reveals an inverse correlation between MTAP and BCAT1 expression in PDAC, and high BCAT1 expression is associated with poor prognosis in patients with PDAC. Collectively, these findings identify the role of BCAT1 as a key regulator mediating metabolic reprogramming in MTAP-deficient PDAC and support BCAT1 as a potential therapeutic target.

Tubulointerstitial fibrosis predicts irreversible kidney function loss in diabetic kidney disease (DKD), but adipose-derived signals that shape fibrogenesis are poorly defined. Here, we show that perirenal fat (PRF), an adipose depot contiguous with the kidney, is enriched for β3-adrenergic receptor (ADRB3) and that ADRB3 expression is reduced in human DKD and male mouse DKD models. In db/db and streptozotocin/high-fat diet mice, increased PRF mass associates with albuminuria and serum creatinine, whereas PRF removal attenuates tubular lipid accumulation, mitochondrial injury and fibrosis. Brown adipocyte-lineage ADRB3 deletion enlarges PRF and increases adipocyte TNFα release by suppressing Bcat2-dependent branched-chain amino-acid catabolism through CREB1/METTL3-mediated m6A regulation. ADRB3 activation or PRF-restricted ADRB3 restoration reduces PRF inflammation and renal fibrosis, while iBAT-restricted restoration does not reproduce this renal protection. These findings identify a PRF ADRB3-Bcat2/BCAA-TNFα pathway that contributes to diabetic renal fibrosis.

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a chronic relapsing intestinal inflammatory disorder driven by complex interactions among host genetics, immune dysregulation, and gut microbiota dysbiosis. The functional contribution of microbial metabolites beyond short-chain fatty acids and bile acids remains incompletely understood. A critical and unresolved question is whether microbiota-associated amino acid metabolites are merely passive indicators of dysbiosis or active drivers of intestinal inflammation and tissue repair. In this review, we summarize recent advances in the roles of microbiota-associated amino acid metabolites and their derivatives in IBD, highlighting that amino acid metabolites constitute a functionally distinct class of bioactive signaling molecules that operate through four representative metabolic networks: tryptophan metabolism, aspartate-related metabolism, branched-chain amino acid (BCAA) metabolism, and arginine-polyamine metabolism. We synthesize recent clinical metabolomic data and identify reductions in tryptophan-derived indoles, glutamate, histidine, and selected BCAAs across IBD clinical cohorts and sample matrices, whereas metabolites such as serine, proline, and polyamine degradation products are frequently elevated or associated with disease activity or therapeutic response. Mechanistically, microbiota-associated amino acid metabolites are implicated in intestinal homeostasis and IBD pathogenesis through multifaceted pathways, including modulation of intestinal epithelial barrier integrity (e.g., cell-cell junction, mucus secretion, and stem cell-driven mucosal repair), innate and adaptive immune responses, host-pathogen interactions, and extraintestinal inflammatory signaling (e.g., systemic inflammation, and brain-gut axis communication). Finally, we highlight current challenges and limitations in achieving a causal understanding of microbiota-associated amino acid metabolic alterations in IBD, particularly regarding their origin, spatial distribution, and functional relevance, as well as their potential utility for disease stratification and treatment-response assessment, and discuss how these insights may inform the future development of next-generation biomarkers and precision therapeutic strategies tailored to individual metabolic phenotypes in IBD.

During swine gestation, the placenta serves as the sole interface for nutrient, gas, and signaling molecule exchange between the dam and fetuses, and its function critically determines pregnancy outcomes. Branched-chain amino acids (BCAAs)-leucine, isoleucine, and valine-are substrates for protein synthesis, precursors for glutamate and glutathione, and signaling molecules that activate the mechanistic target of rapamycin (mTOR) pathway. This review synthesizes current evidence on BCAA transport, catabolism, and signaling in the porcine placenta, organized around four mechanistic axes: transporter-mediated transplacental transfer, local catabolism supporting energy production and antioxidant defense, mTORC1-dependent regulation of growth and differentiation, and modulation of endocrine and immune homeostasis. Both deficiency and excess of BCAAs compromise placental function, contributing to intrauterine growth restriction and metabolic programming abnormalities through a U-shaped dose-response relationship. Critical knowledge gaps remain, including the reliance on rodent and in vitro models, the absence of standardized supplementation protocols and dose-response data, unaddressed confounders (parity, litter size, environment), and the lack of formal power analyses or meta-analytic synthesis. We propose precision dietary strategies to optimize BCAA supplementation during gestation for improved reproductive performance in swine.