Methionine restriction (MetR) attenuates the severity of numerous age-related diseases and extends lifespan across multiple species. Implementing MetR in humans remains challenging due to the low palatability of MetR diets, unfavorable side effects associated with continuous dietary MetR, and interindividual variation in factors that can diminish its efficacy, including microbiota activity, compensatory effects from cysteine, and methionine transfer from neighboring cells. Several novel approaches that target methionine metabolism have been developed – including small molecules, synthetic biotics, and xenotopic tools – with some already translated into early-stage clinical trials. In this review, we discuss a variety of approaches that either produce or mimic MetR, as well as their potential applications for human healthspan improvement.

Formate (the anion of formic acid) is a short-chain monocarboxylic acid. In eukaryotes, it represents the predominant transferable form of one-carbon (1C) units between the mitochondrial and cytosolic compartments. At the cellular level, formate is generated mainly through serine catabolism. At the whole-body level, it is derived from multiple amino acids, anaerobic fermentation by gut bacteria, and the detoxification of methanol and formaldehyde.

Recent work by Yoneshiro et al. links brown adipose tissue (BAT) activity to environmental temperatures during conception, highlighting intergenerational influences shaping BAT function. Here we explore how these findings translate into a cardiometabolic health phenotype and discuss how it can be mediated through sperm epigenetic programming.

Childhood development and pubertal milestones continue to be pillars of pediatric growth monitoring, but increasing trends in childhood obesity and precocious puberty indicate that existing ‘normal’ criteria may be misleading. Here, we suggest a shift from anthropometry-based growth references to metabolically informed benchmarks that better reflect long-term health outcomes.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease posing a major global health concern, closely related to the rising prevalence of obesity. Liver fibrosis is the primary determinant of adverse outcomes in MASH. The increasing worldwide prevalence, economic impact, and adverse outcomes of MASH-associated fibrosis have spurred extensive research to elucidate its pathogenesis and to address its treatment. However, the intricate mechanism driving the transition from metabolic dysfunction to clinically significant fibrosis is not fully understood. Moreover, effective therapies, particularly direct antifibrotic agents, are still lacking, despite the recent approval of resmetirom and semaglutide for MASH-associated fibrosis. Here, we review current insights into the mechanism of MASH-associated fibrosis and provide a comprehensive overview of emerging therapeutic strategies.

CD8+ T cells are vital for antiviral and antitumor immunity, yet in hostile microenvironments, they experience metabolic stress, leading to mitochondrial damage, metabolic dysregulation, and chromatin remodeling that cause immune dysfunction. Aging further exacerbates these processes, with intrinsic metabolic collapse and extrinsic environmental factors jointly impairing T cell immunity. Metabolites orchestrate key epigenetic modifications, shaping transcriptional programs essential for T cell differentiation and memory formation. This review explores the interconnected metabolic and epigenetic mechanisms governing CD8+ T cell fate decisions, emphasizing how mitochondrial dysfunction, metabolic inflexibility, and nutrient competition drive CD8+ T cell exhaustion, senescence, and age-associated dysfunction. Understanding these metabolic–epigenetic circuits offers novel therapeutic avenues, including metabolic reprogramming and senescence-targeted strategies, to rejuvenate immune responses and enhance immunotherapy outcomes.

The molecular mechanisms underlying sex differences in acute kidney injury (AKI) remain incompletely understood. In a study recently published in Nature, Tonnus et al. reported that 17β-estradiol (E2) induces an anti-ferroptotic state in renal tubules through both genomic and non-genomic mechanisms, thereby providing renal protection against AKI.

Type 2 diabetes (T2D) manifests as profound systemic metabolic dysregulation. Mounting evidence indicates T2D significantly impairs T cell immunity, compromising both protective immune responses and immune homeostasis. This dysfunction stems from the multitude roles of metabolites in T cell biology: energy substrates, signaling molecules, and epigenetic regulators. In this review, we synthesize current evidence on how the metabolic hallmarks of T2D (hyperglycemia, hyperinsulinemia, and dyslipidemia) reprogram T cell metabolism and their functionalities. Notably, most patients with T2D receive combination antidiabetic therapies which not only correct systemic metabolism but also exert direct immunomodulatory effects on T cells. Unraveling the interplay between disease-driven metabolic perturbations and pharmacologically induced immunomodulation is essential to advance therapeutic strategies that restore immune competence while preserving immunoregulatory balance.

Metabolites are donors of epigenetic modifications. Zhao et al. demonstrated that an ELMSAN1 regulated nuclear pyruvate dehydrogenase complex (nPDC) generates an independent nuclear acetyl-CoA pool dedicated to histone acetylation. Disrupting ELMSAN1–nPDC interaction reprograms histone acetylation and impedes tumor progression, highlighting the regulation of epigenetics and cell signaling by targeting compartmentalized metabolism.

Advances in the immunometabolism field have shown that infiltrated immune cells play a pivotal role in the development and function of thermogenic adipose tissue (TAT), including brown and beige fat. However, scarce research has focused on the role that organized lymphoid structures, like lymph nodes and lymphatics vessels, may exert on TAT. In this review we summarize the evidence suggesting that a significant link exists between the lymphoid tissues and adipose tissue, and we describe the most important in vitro and in vivo findings indicating that organized lymphoid tissues also play an important role in TAT biogenesis and function, raising relevant questions which are still unsolved in this emerging field.

Glucose sensing and signaling are central to cellular metabolic machinery for the regulation of metabolic homeostasis. Glucose sensing has been almost always assumed to be coupled with glucose metabolism; however, recent findings have unraveled metabolism-independent sensing mechanisms. Here, we discuss whether glucose transporters (GLUTs) and sodium-glucose co-transporters (SGLTs) may also function as glucose sensors independent of their roles in transporting glucose. Moreover, we review the emerging roles of G protein-coupled receptors (GPCRs) in sensing glucose and, consequently, initiating its signaling pathways in a cell-specific manner. Altogether, this review offers insights into the newly identified glucose sensing mechanisms and highlights the therapeutic potential of targeting the downstream glucose signaling pathways for more efficient treatment of diabetes, obesity, and their complications.

Biliverdin reductase-A (BVRA) is a pleiotropic enzyme traditionally known for its antioxidant role in the heme degradation pathway. Recent findings have redefined BVRA as a master regulator of insulin signaling, acting as a kinase, scaffold, and redox-sensitive integrator of metabolic cues. BVRA modulates key nodes of the insulin cascade and sustains mitochondrial and synaptic function. Notably, BVRA loss precedes the accumulation of canonical markers of insulin resistance both peripherally and in the brain. Here we discuss how BVRA could represent an early cross-tissue biomarker of metabolic vulnerability. Its dysfunction contributes to mitochondrial stress, impaired proteostasis, and cognitive decline, thus linking metabolic and neurodegenerative disorders.

The human gut microbiome is a complex microbial ecosystem which has a profound impact on host health and disease. The research focus in this area is rapidly moving from taxonomy to functionality, elucidating the biological role of small molecules produced by the gut microbiome in regulating host metabolism. Among these, microbial volatile organic compounds (mVOCs) play several roles in bacterial communication and microbe–host signaling. Volatilomics, the comprehensive study of volatile metabolites, is emerging as a powerful tool for discovering and investigating these interactions. In this review we examine the current understanding of mVOCs in the gut and highlight how dedicated in vitro and ex vivo volatilomics experiments, alongside in vivo studies, can uncover the biological roles for these emerging small molecules.

Taurine is a conditionally essential amino acid with paradoxical roles in cancer, as both tumor and immune cells rely on it for vital functions Here, we discuss the emerging context-dependent functions of taurine and propose therapeutic strategies that leverage or inhibit its metabolism to modulate cancer progression and immunity.

Hepatocyte senescence is increasingly recognized as a key contributor to liver pathophysiology. While traditionally viewed as a state of permanent growth arrest, hepatocyte senescence is now understood to be more dynamic and potentially reversible, particularly during liver repair. In this opinion article, we propose reframing senescence as a continuum rather than a terminal fate. We focus on early stress-responsive states, especially those marked by p21 expression, which may be adaptive or pro-regenerative depending on the context. We highlight the roles of p21-associated secretory phenotypes (PASPs), senescence-associated secretory phenotypes (SASPs), epithelial plasticity, and partial epithelial-to-mesenchymal transition (EMT) in modulating hepatocyte behavior, immune surveillance, and cancer risk. Viewing hepatocyte senescence as a trajectory opens new opportunities for context-specific and temporally targeted therapeutic strategies in liver disease.

Over the past decade, our understanding of cancer metabolism has advanced significantly, revealing a complex and dynamic landscape of metabolic reprogramming that facilitates tumor progression and promotes therapeutic resistance. To survive under stressful conditions, cancer cells undergo crucial metabolic adaptations while also creating vulnerabilities that can be exploited for therapeutic purposes. Here, we discuss the evolving understanding of cancer cell metabolic adaptation in the tumor environment and the recent advances in identifying potential therapeutic mechanisms, including synthetic lethality, post-translational modifications (PTMs), as well as the interplay between metabolism and epigenetics. Furthermore, we discuss the integration of metabolic targeting with immune-based therapies and provide insights underscoring the potential of metabolic interventions to resensitize drug-resistant cancers and enhance efficacy for cancer treatment.

Glucagon receptor (GCGR) antagonism improves glycemic control; however, it also brings adverse effects through unclear underlying mechanisms. Here, we summarize emerging findings about the impact of GCGR blockade on α cells and discuss the challenges and potential of GCGR antagonism on clinical application.

The small intestine has a pivotal role in nutrient absorption, host defense, and endocrine functions, with the maintenance of its homeostasis relying on the synergistic interplay of intrinsic and extrinsic factors. These encompass a highly organized spatiotemporal microenvironment, characterized by a regionalized histological architecture, functionally specialized cell populations, and spatially rhythmic nutrient gradient environments shaped by dietary patterns. While the link between small intestinal dysfunction and a wide range of systemic diseases has been well established, recent advances in spatial omics and dietary interventions have provided unprecedented new insights. Here, we review recent studies to systematically summarize the spatiotemporal regulatory mechanisms of small intestinal physiology, highlighting their important implications for the progression of inflammatory and metabolic diseases.

Brown adipose tissue (BAT) is a compelling therapeutic target against metabolic diseases. Mechanical cues regulate BAT function and may offer novel, non-pharmacological therapeutic approaches. Herein, we discuss the biomechanical pathways underlying BAT activation, highlight advances in mechanotherapeutic strategies, and consider how emerging technologies may enhance these interventions.

Dysregulation of bodyweight systemic metabolism is intrinsically linked to an inflammatory phenotype, with each underpinning the other. Over the past decade, new classes of drug, such as glucagon-like peptide-1 (GLP-1)-based therapies and sodium glucose co-transporter 2 (SGLT2) inhibitors, have entered the clinical management of bodyweight and metabolic disease with great success. With their expanded use, it is emerging that the benefits of these drugs extend beyond metabolic improvements into changes in chronic inflammation, potentially independent of those in metabolism. In this review, we discuss the impact of metabolic drugs on inflammatory comorbidities of metabolic disorders and beyond. We highlight the molecular mechanisms via which these drugs exert their anti-inflammatory actions and discuss their potential repurposing as direct anti-inflammatory agents.