Volume 8 Issue 4, April 2026

Although long-chain acyl-CoA esters are essential to virtually every aspect of lipid metabolism, their regulatory and signalling roles remain underappreciated. These molecules deserve far greater attention than they receive, because their spatially restricted formation and tightly regulated abundance endow them with potent and highly specific metabolic cues.

Two studies published in Nature Metabolism show that dysregulation of specific metabolic enzymes within the pancreas leads to increased oxidative stress, which promotes pancreatic neoplasia in the presence of oncogenic KRAS mutations.

In this issue of Nature Metabolism, Brain, Vigil et al. show that NRF2-induced cystine uptake drives the formation of several cysteine–sugar metabolites. This process acts as a ‘sink’ for free cysteine and can lead to metabolic vulnerabilities and toxicity in NRF2-activated tumours.

In this issue of Nature Metabolism, Diotallevi et al. propose a novel non-canonical function of inducible nitric oxide synthase (iNOS) as a regulator of immune-responsive gene 1 (IRG1, also known as ACOD1) enzymatic activity and the IRG1 protein interactome.

KRAS mutations in colorectal cancers shape an immunosuppressive tumour microenvironment. In this issue of Nature Metabolism, Yang et al. report that TRIP6 phosphorylation-induced glycolysis in KRAS-mutant colorectal cancer impedes CD8⁺ T cell function by the intriguing extracellular lactylation of CD44.

Ageing and genetic predisposition increase the risk of type 2 diabetes (T2D). Two studies published in this issue of Nature Metabolism show that the DNA methylome in islet α and β cells changes with ageing and the development of T2D. Genes associated with these changes are enriched for those linked to α or β-cell function, and to T2D.

Burmese pythons exhibit extreme feeding and fasting patterns, which might be underlain by extreme molecular responses. Untargeted metabolomics of python blood uncovers a conserved metabolite — para-tyramine-O-sulfate — whose levels spike after feeding and that activates hypothalamic neurons in both python and mouse.

Using 10–14 days of time-stamped food intake logs on a smartphone app from more than 20,000 adults, this study shows that both meal timing and food choice are highly variable in real-world settings, with only a small fraction of individuals maintaining consistent first and last eating times or eating the same foods regularly.

This Review discusses the genetics of obesity, highlighting its diverse forms and describing technological advancements in genetic studies that may enable precision medicine strategies to combat obesity.

This Review highlights recent technological advances in measuring dietary food intake, including artificial intelligence-based methods and approaches informed by the gut microbiome.

In the early stages of pancreatic ductal adenocarcinoma (PDAC) development, loss of ALDH1L2 expression elevates reactive oxygen species levels, driving accelerated acinar-to-ductal metaplasia. Decreased ALDH1L2 expression is accompanied by formate overflow, which can be used to monitor PDAC progression.

Temporal profiling of central carbon metabolism during Kras^G12D-driven acinar-to-ductal metaplasia reveals that disruptions in NADPH-producing enzymes accelerate the formation of pancreatic precancerous lesions.

Previously uncharacterized cysteine-derived conjugates, including with endogenous sugar metabolites, accumulate in cancer cells with constitutive NRF2 activation and account for some of the increased cystine uptake that cannot be explained by conventional cysteine metabolism.

This study reveals a non-canonical immunomodulatory function for the enzyme iNOS, based on the direct interaction in mitochondria with the itaconate-producing protein IRG1, which limits itaconate production in mouse and human macrophages

Leveraging pythons as an extreme model of feeding and fasting behaviour, this study uncovers para-tyramine-O-sulphate as a conserved postprandial metabolite that links nutrient intake to energy balance by activating hypothalamic neurons and suppressing food intake in pythons and mice.

This study demonstrates that overexpression of irisin, an exercise-induced myokine, ameliorates obesity and insulin resistance in high-fat-diet-fed mice by increasing local IL-33 production and preserving ST2⁺ regulatory T cells in white adipose tissues.

TRIP6 phosphorylation triggers a signalling cascade that promotes glycolysis in KRAS-mutant colorectal cancer cells. The resulting lactate accumulation drives extracellular lactylation of CD44 on CD8⁺ T cells, thereby compromising their anti-tumour activity.

The authors provide an interactive resource of folate one-carbon metabolism in 37 tissues in germ-free and conventional mice.

Mapping of genome-wide DNA methylation patterns in human islet alpha and beta cells highlights age and type 2 diabetes dependent adaptations and compensatory responses to altered metabolic demands.

Mapping of genome-wide DNA methylation patterns in human islet alpha and beta cells highlights age- and type 2 diabetes-dependent adaptations, and CRISPR-based epigenetic editing strategies validate key targets in human islet beta cells.

An exploratory, observational analysis involving 2.5 million food logs from over 20,000 adults across 2 weeks highlights both consistent and divergent patterns in food habits that may, in turn, influence human health.