Nicotinamide adenine dinucleotide (NAD) occupies a privileged position at the intersection of cellular bioenergetics, redox homeostasis, and signal transduction. Beyond its canonical role in ATP synthesis, NAD serves as an obligate cofactor for enzymes including poly(ADP-ribose) polymerases (PARPs), sirtuins, and CD38, thereby regulating DNA repair, epigenetic remodeling, and inflammatory signaling. Thus, NAD metabolism supports the preservation of cellular homeostasis against oncogenic insults. Malignant transformation, however, imposes substantial biosynthetic and genotoxic stress, often driving metabolic adaptations that amplify NAD production via nicotinamide phosphoribosyltransferase (NAMPT). This endows cancer cells with enhanced proliferative capacity, stress tolerance, and immunoevasive features. Importantly, the dependence of malignant cells on sustained NAD availability constitutes a therapeutically exploitable vulnerability. Accordingly, NAMPT inhibitors, PARP inhibitors, and strategies targeting NAD-consuming ectoenzymes have shown preclinical and, in select settings, clinical efficacy. Here, we critically review the rewiring of NAD metabolism in cancer, associated therapeutic opportunities, and barriers to their clinical exploitation.

Loss of skeletal muscle mass is a major driver of frailty and disability, yet how systemic metabolic cues protect muscle integrity remains unclear. We identify Serpina3n, an adipose-derived adipokine, as a key mediator of the protective effects of nicotinamide adenine dinucleotide (NAD[+]) supplementation against muscle atrophy. Elevation of NAD[+] in adipose tissue activates signal transducer and activator of transcription (STAT)1-dependent transcription of Serpina3n, leading to its systemic release and muscle protection across models of aging, disuse, and cancer cachexia. In muscle, Serpina3n preserves pyruvate carboxylase protein level, promoting anaplerosis, oxidative metabolism, and protein synthesis. These findings define an NAD[+]-responsive adipose-to-muscle signaling axis that links metabolic status to tissue preservation, defining a systemic mechanism by which inter-organ communication maintains muscle integrity and suggesting potential strategies to counteract muscle degeneration.

Ulcerative colitis (UC) remission does not abolish susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD), but the mechanism linking prior intestinal inflammation to delayed liver injury remains unclear. We establish gut-liver axis memory transduction as an epigenetic-cellular-organ cascade in which inflammatory history is molecularly encoded and redeployed across organs. LCN2[+] colonic macrophages persist after colitis resolution and retain heightened glycolysis together with durable histone H3K9 L-lactylation (H3K9la). These macrophages maintain a permissive memory state during remission and traffic to the liver, where they amplify steatosis under subsequent HFD challenge. Mechanistically, BRG1 cooperates with CEBPB at H3K9la-marked chromatin to sustain Lcn2 and Pkm transcription in a feed-forward circuit. Myeloid-specific Smarca4 deletion or pharmacological interruption of macrophage trafficking attenuates macrophage memory and protects against MASLD. Together, our findings define H3K9la-centered macrophage memory as a mobile pathogenic imprint that links prior colitis to increased susceptibility to metabolic liver disease.

UBT251 is a novel triple agonist targeting glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, and glucagon receptors. In this multicenter, randomized, double-blind, placebo-controlled phase 2 trial, 205 adults with overweight or obesity (59.0% women; aged 18-61 years; without type 2 diabetes) received once-weekly UBT251 at 2 mg, 4 mg (initial dose 0.5 mg or 1 mg), or 6 mg, or placebo for 24 weeks. For the primary efficacy endpoint, least-squares mean percentage changes in body weight at week 24 were -19.7% to -13.6% with UBT251 vs. -2.0% with placebo; placebo-adjusted differences were -17.7% (95% confidence interval [CI], -20.8% to -14.6%) to -11.5% (95% CI, -14.1% to -9.0%; all p < 0.001). UBT251 improved waist circumference, body mass index, blood pressure, lipid profiles, and glycemic parameters. The most frequent adverse events were mild-to-moderate gastrointestinal symptoms. UBT251 produced weight reduction with cardiometabolic improvements and an acceptable safety profile, supporting phase 3 evaluation. This study was registered at China Drug Trials Registry (CTR20250288) and ClinicalTrials.gov (NCT07177469).

How nutrients shape gene expression has remained a fundamental question. Wu et al.[1] show that extracellular arginine directly remodels the tRNA-codon axis, controlling codon-dependent translation of major histocompatibility complex class I mRNA independently of canonical amino acid stress signaling. This nutrient-sensing mechanism regulates immunity in colorectal cancer and viral infection while revealing new opportunities for therapeutic intervention.

In a recent issue of Nature, Desharnais and colleagues show that diet-dependent remodeling of the gut microbiome promotes anti-tumor immunity and may explain the enhanced efficacy of immune checkpoint blockade observed in obesity. Their study identifies dietary intervention as a promising strategy to optimize the host for cancer immunotherapy.

Sawada et al. show that glutamine metabolism through glutaminolysis restrains O-GlcNAcylation and pathogenic inflammatory cytokine production by hepatic CD4[+] T cells during MASLD. Glutamine supplementation restores hepatic glutamine availability and limits liver injury, and these findings reveal a tissue-specific metabolic checkpoint that restrains inflammatory T cell function during steatohepatitis.

Whether dietary macronutrient content has metabolic benefits beyond weight loss is unknown. In this issue, a carefully controlled trial demonstrates that a higher-protein, lower-carbohydrate dietary pattern improves hepatic glucose and lipid metabolism in people with prediabetes and steatosis compared to a lower-protein, high-carbohydrate diet, even though all groups lost 10% of body weight.

Immunometabolism has rapidly evolved from an emerging area within immunology into a topic that not only impregnates most aspects of immune research but also reveals itself as a defining feature of the immune response. At the European Immunometabolism Conference celebrated in June, we asked some of the speakers to share their personal journey as researchers in this field and what questions they are currently working on.

Fungi are crucial components of the human gut microbiota. Here, we investigated the role of fungi in metabolic dysfunction-associated steatotic liver disease-associated hepatocellular carcinoma (MASLD-HCC). Rhizopus arrhizus was the top enriched fungus across the progression from MASLD to MASLD-HCC, accelerating tumorigenesis in multiple mouse models. R. arrhizus-conditioned medium increased cell proliferation while reducing cell cycle arrest and apoptosis in human MASLD-HCC cells. Kynurenic acid (KYNA) was identified as the crucial metabolite generated from R. arrhizus, and its upregulation was confirmed in portal vein, liver tissues, and stools of R. arrhizus-treated mice. KYNA promoted the proliferation of MASLD-HCC cells and accelerated tumorigenesis in mice. Mechanistically, KYNA directly bound to IQ motif containing GTPase activating protein 1 (IQGAP1) in tumor cells and activated the oncogenic mitogen-activated protein kinase (MAPK) signaling pathway, thereby facilitating MASLD-HCC development. In summary, R. arrhizus is a pathogenic fungus that promotes MASLD-HCC by producing KYNA. Blocking this host-fungi interaction is a potential therapeutic strategy to suppress MASLD-HCC.