Metabolic remodelling underlies tumour progression. However, how metabolites act as signalling molecules to support cancer cell proliferation remains unclear. Here we show that argininosuccinate (ASA), a key intermediate of the urea cycle, promotes purine nucleoside biosynthesis in tyrosine kinase-driven haematological malignancies. Mechanistically, BCR–ABL phosphorylates argininosuccinate synthase 1 (ASS1), which increases ASA production from citrulline. ASA directly binds cytosolic 5′-nucleotidase II (NT5C2) and enhances its nucleosidase activity. The resulting purine nucleosides serve as a carbon source for glycolysis and the tricarboxylic acid cycle, which supports leukaemia cell proliferation under glucose-replete conditions. Loss of ASS1 or NT5C2 disrupts central carbon metabolism and inhibits leukaemia progression in vivo, which can be rescued with inosine or adenosine supplementation. Collectively, our findings uncover an ASA–NT5C2 signalling axis linking urea cycle dysregulation to purine metabolism, and identify purine nucleosides as a carbon source in tyrosine kinase-driven haematological malignancies. Argininosuccinate produced by phosphorylated ASS1 allosterically enhances the nucleosidase activity of NT5C2, resulting in increased production of purine nucleosides, which serve as a carbon source in BCR–Abl-positive haematological cancers.
Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the bile ducts that can lead to biliary cancer and end-stage liver disease. PSC is associated with inflammatory bowel disease and an altered gut microbiota. However, the molecular mechanisms underlying gut-liver interactions in PSC remain poorly characterized. Here we show that the gut microbiota-derived metabolite imidazole propionate (ImP) is a disease driver in PSC. Individuals with PSC have higher circulating ImP levels than individuals with related conditions, and high ImP levels predict reduced survival in PSC. Cholangiocytes exposed to ImP show activated mammalian target of rapamycin complex 1 (mTORC1) signalling and secrete pro-inflammatory and pro-fibrogenic factors. Chronic administration of ImP to mice induces liver inflammation and fibrosis through a p38-dependent mechanism, upstream of mTORC1. We propose that chronic exposure to ImP induces cholangiocyte injury, which alone or in concert with other factors causes clinical worsening of PSC. Therefore, targeting ImP production or signalling may represent therapeutic avenues in PSC.
K63-linked ubiquitination (K63) is closely associated with the interaction, intracellular trafficking or activity of tagged proteins. However, its role during metabolic dysfunction-associated steatohepatitis (MASH) is largely unknown. Here we show that UBE2N, a ubiquitin-conjugating enzyme that specializes in creating K63, is downregulated by THAP11 in human and mouse hepatocytes with MASH. While hepatocyte-specific Ube2n deficiency exacerbates western diet-induced MASH and fibrosis via PANoptosis and impaired mitophagy, its overexpression reverses these pathological phenotypes and restores hepatic homeostasis. Mechanistically, UBE2N increases PARKIN-mediated K63-p62 at lysine 420, promoting K63-p62 translocation into damaged mitochondria for mitophagic clearance. Ube2n deficiency, conversely, induces cytoplasmic p62 accumulation and NRF2 hyperactivation, driving PANoptosis. Additional Sqstm1 deletion mitigates Ube2n deletion-induced pathologies, highlighting the importance of p62 accumulation for MASH progression. Thus, our results demonstrate that hepatocyte UBE2N is essential for regulation of metabolic stress-mediated mitophagy and PANoptosis, and that p62 is a proof-of-concept target for treating MASH and fibrosis.
Mitochondrial homeostasis is tightly regulated to prevent hepatocyte injury. In this issue of Nature Metabolism, Wang et al. identify UBE2N as a switch that determines whether hepatocytes undergo protective mitophagy or pathogenic cell death in metabolic dysfunction-associated steatohepatitis (MASH).
Neutrophils and neutrophil-derived serine proteases (NSPs), including neutrophil elastase (NE) and proteinase 3 (PR3), are present in visceral fat of individuals and rodents with obesity, yet their roles in energy metabolism remain elusive. Here we show that neutrophil infiltration and NSP activation impair visceral fat browning in response to β-adrenergic receptor stimulation or cold exposure in male mice. Genetic deletion or local pharmacological inhibition of NE with sivelestat rescued visceral fat browning and enhanced thermogenesis. Mechanistically, NE/PR3 directly suppresses beige adipogenesis by arresting cell cycle via CDK4/cyclin D1 downregulation, impairs beige adipocyte differentiation by degrading insulin-like growth factor binding protein-3, and indirectly promotes M1 macrophage polarization. Administration of sivelestat suppressed diet-induced neutrophil infiltration, enhanced cold-induced visceral fat browning and decreased visceral fat content in mice. These findings reveal an unexpected inhibitory role of NSPs in visceral fat browning and suggest the potential of repurposing sivelestat as an anti-obese drug.
Secreted molecules are central regulators of interorgan communication and metabolic physiology. As the field has expanded rapidly, criteria for assigning molecules as bona fide secreted signals and linking them to functions have remained inconsistent. Here, we describe core concepts in secreted factors and how to study them.
Visceral and subcutaneous adipose tissue differ in their propensity for thermogenic remodelling, yet the mechanisms enforcing this depot specificity remain incompletely understood. Yuan et al. identify neutrophil-derived serine proteases as depot-specific suppressors of visceral fat beiging, expanding the role of innate immunity to shaping adipose tissue plasticity.
Enhanced cholesterol synthesis and lipid droplet accumulation are hallmarks of aggressive prostate cancer, yet how tumour cells sense metabolic inputs to dynamically regulate cholesterol homeostasis remains poorly defined. Here we uncover a metabolic signalling mechanism in which prostate cancer cells remodel propionyl-CoA metabolism to support stress adaptation during disease progression. We show that the catabolism of branched-chain amino acid, specifically isoleucine and valine, is the primary source of intracellular propionyl-CoA in prostate cancer cells. Beyond its metabolic role, propionyl-CoA functions as a signalling molecule that stabilizes nuclear sterol regulatory element-binding protein 2 (SREBP2) through site-specific lysine propionylation, thereby enhancing its transcriptional activity. This activation promotes cholesterol biosynthesis, fuels de novo androgen production, and sustains androgen receptor signalling under metabolic and therapeutic stress, including androgen deprivation. Together, our findings establish propionyl-CoA as a key metabolic signal linking amino acid catabolism to cholesterol-driven oncogenic programmes and highlight targeting isoleucine and valine metabolism as a potential strategy to disrupt lipid reprogramming in prostate cancer.
Skeletal muscle is a central determinant of organismal health. Preserving muscle quality is therefore critical for preventing disease and sustaining quality of life across the lifespan. Despite its central role, the field lacks a unifying framework that defines the core properties of skeletal muscle health. Here, we propose a conceptual framework for muscle homeostasis built around seven interconnected hallmarks-metabolism and bioenergetics, proteostasis, genomics, excitability, structure, regeneration and cross-talk-that collectively govern muscle integrity, adaptability and resilience. Each hallmark is mechanistically grounded, quantifiable and potentially modifiable. This framework provides a unifying blueprint for the next generation of precision diagnostics and targeted therapies for preserving skeletal muscle health.
The neural mechanisms integrating cold sensory input with adaptive thermoregulation remain incompletely understood. A new study published in Nature Metabolism identifies cold-activated neurons in the parabrachial nucleus as recipients of cold sensory cues, which coordinate autonomic, metabolic and behavioural cold responses and act as therapeutic targets for metabolic disorders.
Thermoregulation is a fundamental physiological process essential for survival1,2, yet how the brain represents peripheral cold sensory information and coordinates diverse adaptive responses remains incompletely understood3. Here we identify cold-activated neurons in the parabrachial nucleus (hereafter, PBCold neurons) as primary recipients of cold sensory input in the brain, using activity-dependent genetic labelling in mice4,5. PBCold neurons exhibit rapid and sustained activation across a wide range of cold stimuli, indicating persistent encoding of environmental cooling. Transient or permanent silencing of these neurons disrupts cold-induced adaptations spanning multiple domains, including autonomic (brown adipose tissue thermogenesis and tail vasoconstriction), somatic (skeletal muscle shivering), behavioural (cold avoidance), metabolic (cold-induced hyperphagia) and affective (dopamine release to rewarding cool stimuli) responses, and compromises survival under severe cold. Conversely, activating PBCold neurons promotes warmth-seeking behaviour and increases food intake and energy expenditure. Molecular profiling identifies Grp and Trhr as highly specific yet partially efficient markers for PBCold neuron subsets. Together, these findings establish PBCold neurons as a critical hub coordinating cold-responsive adaptations, advancing our understanding of the central mechanisms governing thermal homeostasis.
Academic careers are shaped by scientific discovery, professional networks, mentorship and the challenges of balancing research with personal and professional responsibilities. In this instalment of our Career Pathways series, Adelheid (Heidi) Lempradl and Lauren V. Albrecht share their experiences of building independent research careers and navigating the opportunities and challenges of academia.
How liver metastases evade immunity remains unclear. A new study published in Nature Metabolism reveals that DHHC17-driven laminin 511 palmitoylation and its subsequent secretion blunts neutrophil-mediated killing of metastatic cancer cells, uncovering a druggable immune checkpoint in the liver.
Liver metastases are frequent and challenging to treat owing to the liver's metabolically active and immune-tolerant environment. However, how cancer cells exploit nutrient availability in the liver to evade immune surveillance remains unknown. Here we show that cancer cells use the palmitate availability in the liver to impair the neutrophil antitumour function. Mechanistically, we find that breast and colorectal cancer cells metastasizing to the liver, but not the lung, require the palmitoyltransferase 17 (DHHC17, gene name ZDHHC17) to stabilize laminin-511 enabling its secretion. In turn, neutrophils in the liver metastasis environment respond to laminin-511 by decreasing their cancer cell-killing capacity. Consistently, silencing ZDHHC17 in cancer cells decreases liver metastases only in the presence of neutrophils, while metastasis growth is restored in ZDHHC17-silenced metastases upon injection of laminin-511 or inhibition of neutrophil degranulation. Taken together, we find that liver palmitate not only supports tumour intrinsic processes but also enables immune evasion.
