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Industrialized diets modulate host eating behavior via the microbiome–gut–brain axis

The gut microbiome is an important participant in the gut–brain axis and a key mediator of host–diet interactions that shape feeding behavior. These effects occur through microbial metabolism of dietary components – fiber, sugar, fat, and protein – into bioactive metabolites that influence microbiome–gut–brain signaling. Industrialized diets are enriched in highly processed, energy-dense foods characterized by elevated fat and sugar content and reduced fiber content. These diets have been implicated in altered eating behaviors involving the microbiome–gut–brain axis. We propose that different ratios of dietary substrates in industrialized diets perturb the microbiome–gut–brain axis, thereby driving changes in microbial metabolite production and downstream signaling with behavioral consequences. Integration of microbiome and neuroscience methodologies will help to delineate the causal mechanisms by which diet shapes interoceptive signaling and eating behavior.

A metabolic perspective on cuproptosis

Copper (Cu) is an essential trace element that plays a fundamental role in various biological processes, including electron transfer and enzymatic reactions. Cu homeostasis is tightly regulated by transporters, including CTR1 and ZnT1, that mediate Cu uptake, as well as by intracellular Cu chaperones and exporters such as ATP7A and ATP7B. Excessive accumulation of Cu can lead to cuproptosis, a form of regulated cell death characterized by Cu-induced lipoylated protein aggregation and degradation of Fe–S cluster proteins. We discuss how recent insights into Cu metabolism and cuproptosis have expanded our understanding of Cu homeostasis, and present new opportunities for the treatment of human diseases involving Cu imbalance, including Menkes and Wilson's diseases, neurodegenerative conditions, and cancer.

Metabolic-immune microenvironment crosstalk mediating ICI resistance in MASH-HCC

As a pivotal immunotherapy modality, immune checkpoint inhibitors (ICIs) have demonstrated significant clinical efficacy in a variety of malignant tumors, including viral hepatocellular carcinoma (HCC). However, metabolic-associated steatohepatitis-related hepatocellular carcinoma (MASH-HCC) is significantly resistant to ICI, its metabolic-immune crosstalk mechanisms have not been systematically defined, and methods to improve the efficacy of ICI in this context are lacking. Thus, here we elucidate the microenvironmental features of MASH-HCC, focusing on tumor metabolic-immune crosstalk mechanisms such as metabolic reprogramming, metabolic stress, fibrosis, and the gut–liver axis, and summarize clinical and preclinical studies currently assessing whether metabolic drugs may help with overcoming ICI resistance and improving clinical efficacy against MASH-HCC.

A multidimensional epidemiological perspective on frailty dynamics and prevention

Frailty, characterized by reduced resilience and increased vulnerability, is a growing public health concern in aging populations. It is increasingly recognized as a dynamic and potentially reversible condition, with transitions between non-frail, pre-frail, and frail states. Recent research has advanced our understanding of frailty through improved multidimensional assessment instruments, trajectories and transitions, and recognition of key risk factors. Here, we synthesize current epidemiological evidence, emphasizing the fluctuating nature of frailty and the potential for early intervention to halt or reverse its progression. We discuss both modifiable and non-modifiable contributors and highlight intervention strategies focused on physical activity, nutrition, and social and environmental support, and aim to inform future directions from a dynamic perspective for prevention and precision management of frailty.

Noncanonical clock regulators control stress responses in digestive diseases

The digestive system is essential for nutrient absorption, processing, and waste elimination. The expression of many genes and physiological processes within this system exhibits a 24-h rhythmicity. However, modern lifestyle factors, such as jet lag, shift work, and irregular eating patterns, significantly disrupt these rhythms, triggering various stress responses and contributing to numerous digestive disorders. Here, we focus on emerging studies on noncanonical clock regulators involved in stress responses, integrate these novel findings into the established model of the core circadian clock, and highlight recent advances in the development of novel therapeutics targeting these 24-h regulators. In addition, we discuss the optimized timing of dietary interventions and drug administration, collectively known as chronotherapy, as a promising approach for managing digestive diseases.

Exercise pills for cardiometabolic health cannot mimic the exercise milieu

Physical exercise can play an important role both in primary and secondary cardiovascular disease prevention by virtue of its multisystem effects. These beneficial adaptations at the whole-body level include improvements in mitochondrial health, vascular function, and autonomic balance, together with attenuation of inflammation and the release of ‘exerkines’ with pleiotropic effects. Thus, several research groups have attempted to develop so-called ‘exercise pills’ or ‘exercise mimetics’: that is, substances that are theoretically capable of reproducing some of the cardiometabolic benefits associated with regular exercise. In this review we summarize pharmacological and phytochemical agents which, when used alone or in combination with exercise, may improve cardiometabolic health. We also discuss the current gaps and future steps needed to translate these findings into therapeutic applications.

Triglyceride-based lipotoxicity in the pathophysiology of chronic diseases

Since the introduction of the concept of 'lipotoxicity' 30 years ago, it has become widely accepted that ectopic triglyceride deposition is a key contributor to metabolic diseases. Subsequently, clinical observations have also revealed that triglyceride deposition can occur in a wide range of tissues and organs, including liver, pancreas, kidney, bone, thyroid and sex glands. However, these ectopic triglycerides were long regarded as inert reservoirs. Recently, progress in the field has continued to demonstrate the pathogenic potential of ectopic triglycerides within their deposition sites. Thus, lipotoxicity-related disorders have been extended to include pancreatitis, renal disease, osteoporosis, hypothyroidism, and infertility. In this review, we aim to provide an updated summary on the contribution of triglyceride-based lipotoxicity to chronic diseases.

Repurposing metabolic drugs as anti-inflammatory agents

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.

Spatiotemporal coordination between local flux and systemic homeostasis in the small intestine

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.

Exploiting metabolic vulnerabilities to improve cancer therapeutics

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.

Redefining senescence through hepatocyte fate changes in liver diseases

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.

Decoding microbial volatile signals in host–microbiome crosstalk

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.

Biliverdin reductase-A is a key modulator in insulin signaling and metabolism

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.

Contribution of metabolism-independent glucose sensing to metabolic homeostasis

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.

The interplay between organized lymphoid structures and thermogenic adipose tissue

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.