Metabolic dysfunction-associated fatty liver disease (MAFLD) and its more severe manifestation, metabolic-associated steatohepatitis (MASH), are intimately linked to disturbances in lipid metabolism. Although downstream signaling pathways of epidermal growth factor receptor (EGFR), including extracellular signal-regulated kinase (ERK) and proto-oncogene serine/threonine kinase (RAF1), exhibited heightened activation during MASH progression, their specific roles and underlying mechanisms in driving MASH pathogenesis remain inadequately elucidated.

Heart failure (HF) progression involves complex metabolic and multi-organ alterations, but the specific adaptations in adipose tissue are not fully understood.

The "obesity paradox" in cancer remains controversial amid inconsistent meta-analyses. This umbrella review re-analyses evidence across 13 malignancies using pre-specified credibility criteria to clarify associations.

Overweight and obesity represent major modifiable determinants of atrial fibrillation (AF) incidence and arrhythmia outcomes after AF ablation therapy. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and their next-generation co-agonists exert potent weight-lowering and cardiometabolic effects and may therefore confer antiarrhythmic effects. This meta-analysis aimed to quantitatively assess the effect of GLP-1-based therapies on the risk of AF among individuals with overweight or obesity.

Heart failure with preserved ejection fraction (HFpEF) is increasingly recognized as an age-predominant syndrome characterized by diastolic dysfunction despite preserved systolic performance. In the aged myocardium, fatty acid oxidation capacity declines, while glycolytic flux increases; however, impaired pyruvate oxidation limits mitochondrial glucose oxidation, resulting in suboptimal ATP yield per oxygen molecule and worsening energetic inefficiency. Mitochondrial deficits, marked by reduced biogenesis, NAD depletion related to reduced sirtuin activity and consequent hyperacetylation of oxidative enzymes, and impaired electron-transport capacity, further diminish bioenergetic reserve and elevate reactive oxygen species generation. Concurrently, inflammaging and proteostatic collapse promote chronic low-grade inflammation, misfolded protein accumulation, and myocardial fibrosis, collectively contributing to increased ventricular stiffness and progressive HFpEF development. Therapeutic strategies targeting these interconnected pathways show considerable promise. Preclinical studies suggest that interventions such as NAD precursor supplementation, mTORC1 inhibition, and β-hydroxybutyrate administration can ameliorate HFpEF-like phenotypes by improving mitochondrial efficiency and reducing inflammation. SGLT2 inhibitors and GLP-1 receptor agonists confer clinically proven benefits in HFpEF, likely via systemic metabolic reprogramming toward more oxygen-efficient substrates and attenuation of inflammation. This review underscores the critical role of aging-associated metabolic and mitochondrial derangements in HFpEF pathogenesis and highlights mechanistically tailored interventions as the next frontier in managing this challenging, age-related syndrome.

The ubiquitous transcription factor Ying Yang 1 (YY1) plays a fundamental role in multiple biological processes and is believed to regulate up to 10 % of all human genes. In thermogenic brown adipose tissue, YY1 has been linked to controlling mitochondrial gene expression and regulating cellular oxidative respiration, protecting against diet-induced obesity and alterations in energy balance. The role of YY1 in non-thermogenic, white adipose tissue, on the other hand, remains largely unknown. Here, we show that adipocyte-specific induction of YY1 promotes dysfunctional adipose tissue and systemic insulin resistance in mice. Long-term YY1 induction in mature adipocytes leads to reduced weight gain, systemic insulin resistance, and increased liver steatosis in comparison to control littermates. In contrast, brown adipose tissue-specific YY1 overexpression has little effect on mice fed a high-fat diet. In an obesogenic environment, acute ectopic adiponectin promoter-driven YY1 expression promotes weight loss, cell death, and adipose tissue inflammation. Underlying the observed reduction in adipose tissue mass, we find that YY1 controls gene networks related to adipose tissue expansion, lipid anabolic pathways (hypertrophy), and hyperplasia (adipogenesis). Taken together, our results demonstrate novel roles of Yy1 in white adipose tissue. This versatile transcription factor regulates central aspects of white adipose tissue biology that are essential for maintaining whole-body physiology.

Innate immune receptors play a pivotal role in modulating immune responses during the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). This study aims to comprehensively investigate the role of the C-type lectin receptor DC-specific ICAM3-grabbing non-integrin (DC-SIGN) in MASLD progression.

Ambient air pollution aggravates cardiovascular-kidney-metabolic (CKM) disorders and sarcopenia, yet the shared genetic and epigenetic mechanisms that underlie their frequent co-occurrence remain poorly understood.

Arginine, as a semi-essential amino acid, plays a pivotal role in bone metabolism and orthopedic diseases. Beyond its function in protein synthesis, arginine serves as a crucial precursor for Nitric Oxide (NO), polyamines, and proline, profoundly influencing osteoblast differentiation, osteoclast activation, immune responses, and angiogenesis. Research indicates that abnormalities in arginine metabolism-such as imbalances in NO synthase activity, upregulation of arginase, or abnormal expression of protein arginine methyltransferases-are closely associated with the onset and progression of osteoporosis, rheumatoid arthritis, osteoarthritis, and bone tumors. Simultaneously, the arginine pathway intertwines with oxidative stress, inflammatory responses, and epigenetic regulation, forming a complex "metabolism-immunity-bone" network. In materials science, arginine has been integrated into various biomaterial systems, including Poly (lactic-co-glycolic acid) (PLGA) scaffolds, chitosan hydrogels, hydroxyapatite composites, and RGD-functionalized polymers, significantly enhancing osteogenic, angiogenic, and immunomodulatory capabilities. Despite ongoing research advancements, challenges persist in understanding the environment-dependent effects of arginine, optimizing dosage, and achieving clinical translation. This review systematically summarizes the mechanistic roles of arginine in bone metabolism regulation and its application progress in engineered materials, offering novel therapeutic insights and research directions for preventing and treating diseases such as osteoporosis, arthritis, and bone tumors.

The role of hypothalamic branched-chain amino acid (BCAA) catabolism in the maintenance of energy homeostasis remains elusive. By using Mendelian randomization, we found that genetically predicted branched-chain keto acid dehydrogenase E1α subunit (BCKDHA) expression in the hypothalamus was negatively associated with fat mass. Hypothalamic deletion of BCKDHA (Bckdha) leads to increased fat mass, reduced energy expenditure, and blunted browning of white adipose tissue in mice, with decreases of thyrotropin-releasing hormone (TRH) expression in the paraventricular nucleus (PVN) and hypothalamic-pituitary-thyroid (HPT) axis activity. Mice with adeno-associated virus-mediated deletion of BCKDHA in the PVN neurons displays a similar metabolic phenotype to Bckdha mice. TRH supplementation ameliorates the abnormal phenotypes of Bckdha mice. Defective BCAA catabolism in the hypothalamus results in hypoacetylation of histone H3 lysine 27 (H3K27) due to decreased acetyl-CoA content, reducing its binding to the Trh promoter. Our study highlights the crucial role of hypothalamic BCAA catabolism in maintaining energy homeostasis through HPT axis.

People living with human immunodeficiency virus (HIV) (PLWH) on antiretroviral treatment (ART) have an increased risk of atherosclerotic cardiovascular disease (CVD) and metabolic syndrome (combinations of adiposity, insulin resistance, hypertension, and dyslipidemia). Together, CVD and metabolic syndrome constitute the cardiometabolic syndrome. Traditional CVD risk factors and high-density lipoproteins (HDL) alterations seem to contribute to the elevated CVD risk. Cumulative evidence suggests that assessing HDL function instead of HDL cholesterol levels (HDL-C) may be a better way to assess cardiometabolic risk. In HIV infection, HIV-1, ART, and the altered function of organs like the liver, gastrointestinal tract, and immune system affect the proteome, lipidome, and metabolism of HDL, ultimately leading to its dysfunction. However, the impact of altered HDL functions on PLWH remains unclear and whether HDL dysfunction reflects and/or contributes to cardiometabolic syndrome in HIV infection (bidirectional cross talk regarding how HDL function impacts the cardiometabolic syndrome and vice versa). Large cohorts of PLWH with variable CVD risk using independent assays of HDL function are needed to elucidate the bidirectional crosstalk between HDL functions and cardiometabolic syndrome. Developing novel treatments to improve HDL function in PLWH may have multiple beneficial results, reducing chronic inflammation and cardiometabolic risk in PLWH. This review aims to summarize the scientific evidence related to the role of HDL functions in HIV and how therapeutic targeting of HDL dysfunction may contribute to reduced cardiometabolic risk in PLWH.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent and increasingly chronic liver disorder with increasing global incidence, closely linked to prolonged high-fat diet (HFD)-induced metabolic impairment. Although imeglimin, an antidiabetic agent known to improve insulin resistance, has demonstrated therapeutic potential in metabolic diseases, its effects and underlying molecular mechanism in MASLD remain unclear.

Ferroptosis, a distinct form of iron-dependent cell death characterized by lipid peroxidation, has emerged as a pivotal regulator in the pathogenesis of liver diseases. It functions both as a driver of hepatocyte injury in chronic liver disorders and as a therapeutic vulnerability in hepatocellular carcinoma. This review provides a comprehensive analysis of the regulatory networks of ferroptosis, shaped by both epigenetic and post-translational modifications. Specifically, we detailed how RNA and DNA methylation, non-coding RNAs, histone acetylation and post-translational modifications dynamically modulated the expression, stability and activity of ferroptosis-related molecules, especially for glutathione peroxidase 4, solute carrier family 7 member 11, acyl-CoA synthetase long-chain family member 4 and transferrin receptor 1. By dissecting these multilayered regulatory mechanisms, we delineated how distinct modifications operated, either promoting or suppressing ferroptosis across various liver diseases. Furthermore, we summarized recent advances in therapeutic interventions targeting ferroptosis-related pathways, including their pharmacological mechanisms, efficacy in preclinical models and limitations in clinical translation. Special emphasis was also placed on the complexity of modifications, disease-stage specificity and the topology of modification sites in shaping ferroptosis sensitivity. Collectively, this review highlights ferroptosis as a dynamic and therapeutically actionable within liver pathology and underscores the potential of targeting regulatory modifications to refine strategies for disease intervention.

Vascular smooth muscle cell (VSMC)-derived foam cell formation is a major contributor to atherosclerosis progression and plaque instability. Meteorin-like protein (METRNL), a secreted organokine with known metabolic and anti-inflammatory effects, has been linked to cardiovascular protection, but its role in atherosclerosis is not well defined. This study investigated the function of METRNL in VSMC-derived foam cell formation and atherosclerosis and explored the underlying signaling mechanisms.

Sufficient nutrient supply is important for the maintenance of non-lymphoid tissue resident CD8+ T cell homeostasis, but the role of labile iron remains unclear. Here, we find adipose tissue CD8+ T cells exhibit elevated labile iron and mitochondrial Fe2+ compared to splenic counterparts, driving high ROS and IFNγ production. In obesity, an increase in Fe2+ influx into mitochondria enhances adipose tissue CD8+ cell functions, but weight loss normalizes CD8+ cell iron metabolism. Ncoa4 knockout reduces labile iron, blunting ROS and IFNγ production, while Fth1 knockout elevates Fe2+ and ROS, elevating IFNγ production. CD8+ cell-specific activation of NRF2 restores iron homeostasis by upregulating ferritin and promoting oxidative detoxification, suppressing adipose tissue CD8+ T cell accumulation and IFNγ production. Finally, NRF2 overexpression in CD8+ T cells attenuates obesity-related adipose tissue inflammation and metabolic disorders. These results highlight the crucial role of labile iron supply in adipose tissue CD8+ T cell homeostasis.

Foam cell formation has traditionally been attributed to macrophages; however, emerging evidence highlights vascular smooth muscle cells (VSMCs) as another significant contributor. Here, we found that TMEM41B is significantly upregulated in VSMCs of both human atherosclerotic (AS) lesions and murine models. Silencing TMEM41B in VSMCs of apolipoprotein E-deficient (ApoE) mice markedly reduced plaque size and macrophage infiltration. Overexpressing TMEM41B in cultured VSMCs altered intracellular lipid profiles by stabilizing fatty acid synthase (FASN), a crucial enzyme in fatty acid synthesis, via inhibiting its ubiquitination and degradation. The TMEM41B-FASN axis drove lipid synthesis, promoted intracellular lipid storage, and facilitated the release of pro-inflammatory cytokines. Further, in cultured VSMCs, herpes simplex virus (HSV) infection amplified TMEM41B expression via OCT-1-mediated transcriptional activation, linking viral infection to lipid metabolic reprogramming in vitro. These findings expand the current understanding of VSMC-derived foam cell formation and suggest that targeting the TMEM41B-FASN axis may represent a promising therapeutic strategy for AS, particularly in the context of HSV infection.

The human brain, despite accounting for only 2 % of total body weight, exhibits an exceptionally high lipid content (approximately 20 % of its mass), highlighting the critical role of lipid metabolism in maintaining neural homeostasis and function. Neurodegenerative diseases-including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)-are characterized by progressive neuronal dysfunction and myelin degeneration. These conditions predominantly affect aging populations and represent a growing global health challenge. While aging remains the primary risk factor, compelling evidence now underscores the involvement of dysregulated lipid metabolism in their pathogenesis. However, the precise mechanisms linking dynamic lipid metabolic alterations to disease progression remain incompletely elucidated. This review systematically examines the multifaceted contributions of lipid metabolism to neurodegenerative processes and critically assesses emerging therapeutic strategies that target lipid pathways for the treatment of neurodegenerative disorders.

As a devastating complication, diabetic foot ulcer (DFU) is characterized by chronic, nonhealing wounds due to vasculopathy and neuropathy. It has emerged as a most challenging chronic disease worldwide, affecting millions of people worldwide. The higher mortality and disability rates urgently require innovative therapeutic strategies. Recently, different from nanotechnology, metabolic reprogramming is believed to be associated with the occurrence and progression of various diseases (including cancer, obesity and neurodegenerative diseases). They can alter their cellular metabolism (involving glucose, lipid, and amino acid metabolism) to cope with different external stimuli and pressures. As a novel potential strategy, metabolic reprogramming also exhibits great potential to improve the wound healing of DFU. This review aims to summarize the current knowledge, biological characteristics, and underlying mechanisms of metabolic reprogramming in DFU. And we propose their potential therapeutic implications to improve wound healing and prevent complications in DFU. In addition, we also highlight the current challenges and the future perspectives.

Calcitonin (CT) is a hormone produced by C cells in the thyroid gland. Its primary function is to regulate bone turnover. However, it is believed to be of little importance to human physiology because its absence following thyroidectomy has no dramatic effects. It was used in the treatment of osteoporosis but has now largely been replaced by bisphosphonates and monoclonal antibodies. However, some studies suggest that CT may have additional functions, such as those related to bone structure, osteoprotection, and pain management. This review summarizes CT synthesis and function and discusses its role and that of its precursor, procalcitonin, as biomarkers. Procalcitonin detection has advantages over some established markers in sepsis management and due to its greater stability, it is also an alternative to CT for managing medullary thyroid carcinoma. Recent research has raised the possibility that procalcitonin could serve as a direct molecular target for treating sepsis. Potential roles of various regulatory peptides released by C cells that may contribute to paracrine fine-tuning of thyroid hormone secretion by follicular thyrocytes are considered. Health-care providers should inform patients that despite optimal thyroxine replacement therapy, subtle symptoms may still occur due to the absence of C cells.

Prenatal caffeine exposure (PCE), stemming from widespread maternal intake of caffeine-containing substances, has emerged as a major pharmacological stressor affecting fetal neurodevelopment. Although epidemiological studies have consistently linked PCE to cognitive impairments and emotional deficits in offspring, the underlying mechanisms have long been confined to direct adenosine receptor antagonism, failing to explain the persistent neurodevelopmental consequences. Here, using cross-species models (rat PCE, astrocyte-specific Abcg1 knockout mice, and glucocorticoid-treated zebrafish) and multi-scale analyses, we demonstrate that PCE activates the maternal-fetal glucocorticoid axis, leading to dysregulation of the GR-miR-130b/301b-PPARγ signaling cascade in hippocampal astrocytes. This disrupts expression of the cholesterol transporter- ATP binding cassette subfamily G member 1 (ABCG1), impairing astrocytic cholesterol efflux and depriving neurons of cholesterol-rich microenvironments essential for synaptic development. Abcg1 knockout mice recapitulate PCE-induced synaptic defects, while astrocyte-specific ABCG1 overexpression or miR-130b/301b inhibition rescues neuronal cholesterol supply and synaptic structure. Luciferase assays confirm that miR-130b/301b directly suppress Pparγ-mediated Abcg1 transcription. Our findings identify the GR-miR-130b/301b-PPARγ-ABCG1 axis as a core mechanism of PCE-induced neurotoxicity, establishing astrocytic cholesterol transport as a potential intervention target and providing a shared molecular framework for evaluating central nervous system risks of glucocorticoid-disruptive agents.