AMP-activated protein kinase (AMPK) is a crucial regulator of cellular energy balance, affecting numerous downstream targets across various subcellular locations. Under cellular energy stress, AMPK becomes fully activated when it binds AMP and is phosphorylated by upstream kinases, including liver kinase B1 and calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), and works to restore metabolic equilibrium. Additionally, CaMKK2 can activate AMPK independent of AMP in response to calcium signaling. In the present review, we summarize how genetically encoded kinase activity reporters for measuring AMPK activity have evolved for a comprehensive measurement of spatial and temporal AMPK activity in single cells. These reporters have provided important insights into AMPK activity dependent upon upstream kinases, location, and signaling cues. We also discuss the use of genetic actuators such as the AMPK inhibitory peptide that can be targeted to suppress AMPK activity at specific compartments. Together, these advances have established AMPK as a key regulator of metabolism with distinct spatial and temporal signaling patterns, suggesting compartmentalization of AMPK activity in the cell.

Celastrol inhibits the immune escape and proliferation of triple - negative breast cancer (TNBC) through the LKB1 - AMPK - PD-L1/MYC signaling pathway.

Gut microbiota-mediated metabolic dysregulation in type 2 diabetes and metabolic syndrome: emerging therapeutic targets beyond glycaemic control.

Ginseng root extract alleviates nonalcoholic fatty liver disease by modulating mitochondrial function and regulating lipid metabolism via the AMPK pathway.

RAB5A regulates cell proliferation and lipid metabolism by modulating mitochondrial ROS via AMPK signaling pathway in ovarian granulosa cells.

Neobavaisoflavone, a functional metabolite derived from valnemulin, ameliorates DSS-induced ulcerative colitis through activation of the AMPK signaling pathway.

Bacterial pneumonia is a common acute respiratory infection. The role of Meteorin-like (METRNL) in bacterial pneumonia is unknown. To investigate the clinical and functional role of METRNL in bacterial pneumonia. METRNL levels were examined in the animals and patients with bacterial pneumonia. Multiple genetic and pharmacologic approaches were used to investigate METRNL-mediated host immune responses during bacterial pneumonia. METRNL production was dramatically suppressed in response to acute bacterial lung infection. METRNL loss increased mortality and bacterial burden during Pseudomonas aeruginosa and Staphylococcus aureus pneumonia, but had no effects on Aspergillus fumigatus and influenza virus pnuemonia. Conversely, METRNL overexpression resulted in decreased mortality and bacterial burden from bacterial pneumonia. Furthermore, therapeutic administration of recombinant METRNL protein improved mortality and bacterial clearance in a neutrophil-dependent manner after bacterial pneumonia. METRNL enhanced bacterial phagocytosis and subsequent killing capacity of neutrophils, and conditional knockout of KIT receptor tyrosine kinase in neutrophils abolished METRNL-mediated protection against bacterial pneumonia. Furthermore, the increased antibacterial functions of neutrophils elicited by the METRNL-KIT axis was mediated through adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. The augmented antibacterial effects of METRNL on neutrophils were also confirmed in humans, and circulating METRNL levels were reduced in patients with bacterial pneumonia, which might serve as a new biomarker for patient stratification and therapeutic guidance. This study suggests that a potential theranostic approach involving METRNL-guided patient stratification and targeted therapy using METRNL rescue therapy may help improve the management of patients with bacterial pneumonia.

The prolonged cold season on the Qinghai-Tibet Plateau poses substantial challenges for most animals, including limited access to natural pasture, reduced appetite, and subsequent weight loss. The polysaccharides that are contained in yeast cell wall (YCW) act as prebiotics, promoting the action and development of beneficial gut microbiota while inhibiting the proliferation of pathogens, thereby maintaining normal gastrointestinal function in animals. This research aimed to examine how incorporating yeast cell wall (YCW) into the diet influences rumen fermentation, the composition of microbiota, and liver metabolism in Tibetan sheep. A total of 30 one-year-old Tibetan sheep, with an mean weight of 30.51 ± 7.07kg, was randomly assigned to groups: a control group and a supplementation of 0.3% YCW group. Each group consisted of 15 sheep. The experimental period lasted for 98 days. The research showed that the addition of YCW increased Dry matter digestibility and average daily gain (ADG) of Tibetan sheep significantly (P < 0.05); the concentrations of propionic acid, acetic acid, total volatile fatty acids, and ammonia nitrogen in the rumen were significantly increased (P < 0.05); In the liver, the mRNA expression of genes associated with gluconeogenesis, including Glucose-6-phosphatase, catalytic subunit (G6PC), Phosphoenolpyruvate carboxykinase 1(PEPCK1), and Fructose-1,6-bisphosphatase (FBP), were significantly increased following YCW supplementation (P < 0.05); the mRNA expression level of Sterol regulatory element-binding protein 1c (SREBP1c), which is involved in lipid metabolism, was significantly decreased (P < 0.05); The inclusion of YCW in the diet reduced the relative abundance of Desulfobacterota and Firmicutes significantly, and increased Prevotella's abundance significantly in the rumen (P < 0.05). Liver metabolites were substantially enriched in the glycerolipid metabolism, glycolysis/gluconeogenesis, and the AMP-activated protein kinase (AMPK) signaling pathway (P < 0.05). YCW supplementation in feed may advance the growth and gain of Tibetan sheep and improve gluconeogenesis. This effect may be ascribed to modifications in the rumen microbiota facilitating propionic acid fermentation, subsequently regulating liver lipid metabolism.

Adenosine monophosphate-activated protein kinase (AMPK) is a central regulator of cellular energy homeostasis that integrates metabolic stress signals arising from nutrient deprivation and other adverse conditions. Dysregulation of AMPK signaling is involved in malignancies, as cancer cells reprogram nutrient acquisition and metabolic pathways to meet heightened bioenergetic and biosynthetic demands. This review synthesizes recent advances in understanding AMPK's dual roles in tumor progression and suppression. The literature was systematically searched in PubMed, Scopus, and Web of Science (mainly from 2010-2025) using relevant keywords. AMPK modulates oncogenic signaling via mTORC1, p53, and FOXO pathways in a context-dependent manner. AMPK serves a dual role, functioning primarily as a tumor suppressor in the early stages of carcinogenesis, while potentially promoting cancer cell survival in certain tumor conditions. AMPK can either inhibit or enhance cancer progression, depending on the specific cell type or condition. AMPK represents a promising therapeutic target for precision oncology through modulation of metabolic pathways.

Objective COVID-19, caused by SARS-CoV-2, is a systemic disease with vascular involvement. The spike protein subunit 1 (S1) has been suggested to contribute to endothelial dysfunction by modulating AMP-activated protein kinase (AMPK) signaling and nuclear factor kappa B (NF-κB) activation, potentially promoting inflammation, thrombosis, and vascular injury. This study aimed to investigate the effects of metformin and phenformin, biguanide drugs with known AMPK-activating properties, on S1-induced inflammatory responses and AMPK/NF-κB pathway modulation in human umbilical vein endothelial cells (HUVECs). Materials and Methods HUVECs were used as a model of the macrovascular endothelium, which is known to exhibit endothelial dysfunction and inflammation associated with vascular complications in COVID-19. Cells were exposed to the S1 protein for 1 and 24 hours, followed by treatment with phenformin (10 µM and 100 µM) or metformin (100 µM and 1000 µM). Cell viability, AMPK activation, NF-κB phosphorylation, and monocyte adhesion were evaluated. Results S1 exposure was associated with increased endothelial cell viability and NF-κB activity, along with decreased AMPK phosphorylation. Metformin, particularly at 1000 µM, was associated with increased AMPK activity and reduced NF-κB signaling and monocyte adhesion. Phenformin (10 µM and 100 µM) showed similar but less pronounced effects. These findings suggest that the S1 protein may contribute to endothelial dysfunction in HUVECs. Metformin, at higher concentrations, may mitigate these effects through modulation of the AMPK/NF-κB signaling pathway. Conclusion Metformin may exert protective effects against S1 protein-induced endothelial inflammation and dysfunction via modulation of AMPK/NF-κB signaling. Further studies are needed to confirm these findings.

Type 2 diabetes mellitus (T2DM) represents a significant global health burden. The natural alkaloid, 1-Deoxynojirimycin (DNJ), abundant in mulberry (Morus alba L.), offers a promising bioactive approach to its early management. This review comprehensively summarises the multifaceted roles of DNJ in modulating the core pathophysiological dysfunctions of T2DM, including impaired glucose and lipid metabolism, insulin resistance (IR), and dysbiosis of gut microbiota. Specifically, DNJ exerts its therapeutic effects by regulating various pathways involved in glucose and lipid metabolism (e.g., phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) and AMP-activated protein kinase (AMPK) pathways), enhancing insulin sensitivity, modulating the gut microbiota, and upregulating transporter proteins. We highlight emerging methodologies, such as network pharmacology, which underscore the pivotal role of the PI3K/AKT and AMPK signalling pathways as primary targets of DNJ in T2DM management. Although this review elucidates multifaceted mechanisms of DNJ in T2DM management, it also identifies critical research gaps, particularly concerning its effects on pancreatic cells, obesity-related T2DM, and mitochondrial energy metabolism. Further investigation in these areas is crucial for fully understanding DNJ’s preventive and therapeutic potential and for the development of related functional foods.

Cancer cells reprogram their metabolism not only through genetic mutations but also via reversible epigenetic modifications that alter gene expression without changing the DNA sequence. AMP-activated protein kinase (AMPK) is a master regulator of cellular energy homeostasis. It plays a crucial role in cancer by modulating key metabolic pathways, including autophagy, lipid biosynthesis, and glucose utilization. Emerging evidence suggests that AMPK is tightly regulated by epigenetic mechanisms, including DNA methylation, histone remodeling, and non-coding RNAs, which influence AMPK gene expression, activation, and post-translational stability. Non-coding RNAs, including long non-coding RNAs, microRNAs, and circular RNAs, often engage in dynamic feedback loops with AMPK, coupling metabolic stress to transcriptional and epigenetic remodeling. In parallel, DNA methylation and histone modifications influence AMPK signaling indirectly through modulation of upstream regulators and directly via chromatin-associated functions of AMPK. Despite extensive characterization of AMPK function in cancer metabolism, the epigenetic mechanism governing its regulation remain comparatively underexplored. Distinct epigenetic signatures associated with AMPK regulation are being explored as a potential therapeutic target. This review provides a comprehensive overview of epigenetic regulation of AMPK in cancer and highlights its potential in the context of metabolic reprogramming and precision oncology.

The identification of direct molecular targets for bioactive dietary components is critical for precision nutrition intervention in metabolic dysfunction-associated steatotic liver disease (MASLD). Fucoxanthin, a marine carotenoid from Sargassum fusiforme, exhibits potent lipid-lowering effects; however, its precise intracellular targets and upstream regulatory mechanisms remain elusive. Herein, using drug affinity responsive target stability (DARTS) coupled with LC-MS/MS, we identified the endoplasmic reticulum (ER) chaperone glucose-regulated protein 78 (GRP78) as a direct binding target of fucoxanthin. Molecular dynamics (MD) simulations and cellular thermal shift assays (CETSA) confirmed a stable interaction, primarily driven by hydrogen bonding at the ARG74 residue. In ob/ob mice and palmitic acid-induced HepG2 cells, fucoxanthin treatment significantly alleviated hepatic steatosis and suppressed ER stress. Mechanistically, the fucoxanthin-GRP78 interaction was found to be indispensable for the subsequent activation of AMP-activated protein kinase (AMPK) signaling. Notably, siRNA-mediated knockdown of GRP78 or pharmacological inhibition of AMPK completely abolished the lipid-lowering and ER stress-relieving effects of fucoxanthin, confirming a causal GRP78-AMPK axis. This study elucidates a novel target-driven mechanism wherein fucoxanthin acts as a GRP78 ligand to restore ER homeostasis and reprogram lipid metabolism. These findings position the fucoxanthin-GRP78 axis as a specific therapeutic target for nutritional strategies against MASLD.

Adaptive thermogenesis is a fundamental defense against obesity through energy dissipation, yet the molecular mechanisms that couple energy sensing to transcriptional control remain incompletely understood. Here, we identify Feimin as a key activator of adaptive thermogenesis that connects AMP-activated protein kinase (AMPK) signaling to nuclear transcriptional regulation in adipose tissue. Upon cold exposure, AMPK phosphorylates Feimin, promoting translocation of Feimin into the nucleus, where it directly interacts with PGC1α to drive thermogenic gene expression. Conversely, obesity attenuates Feimin phosphorylation and nuclear localization, leading to impaired thermogenic capacity. Adipose-specific Feimin knockout abolishes cold-induced thermogenesis and exacerbates diet-induced obesity, phenotypes that cannot be rescued by a nuclear localization-defective Feimin mutant. Together, these findings delineate an AMPK-Feimin-PGC1α signaling axis essential for thermogenic regulation and identify Feimin as a promising therapeutic target for obesity and metabolic disorders.

Maternal hyperglycemia disrupts cardiomyocyte maturation via aberrant nucleotide metabolism and suppression of AMPK signaling.

HighlightsWhat are the main findings?Zika virus (ZIKV) reprograms trabecular meshwork cell metabolism by activating AMPK signaling and promoting lipid droplet (LD) biogenesis.Fatty acid (FA) metabolism regulates infection, where saturated FAs enhance and unsaturated FAs suppress ZIKV replication by affecting viral entry.What are the implications of the main findings?Host metabolic pathways (AMPK, LD, and FA metabolism) are key regulators of ZIKV ocular infection and pathogenesis.These pathways represent potential therapeutic targets for preventing or treating ZIKV-associated ocular complications.Zika virus (ZIKV) remains a significant global public health threat due to its association with severe neurological and ocular abnormalities, including microcephaly and congenital glaucoma in infants. Viruses often exploit host metabolic programs, such as energy and lipid metabolism, to support their replication. However, how ZIKV-driven metabolic reprogramming affects the anterior segment of the eye, especially trabecular meshwork (TM) cells, remains poorly defined. In this study, we investigated the roles of AMP-activated protein kinase (AMPK) signaling, fatty acid (FA) metabolism, and lipid droplet (LD) biogenesis in ZIKV-induced ocular pathogenesis using primary human TM cells and an IFNAR1-deficient mouse model. ZIKV infection triggered time-dependent activation of the LKB1-AMPK-ACC signaling axis and significantly increased LD accumulation. Pharmacological activation of AMPK suppressed viral replication, whereas its inhibition enhanced infection, highlighting an antiviral role for AMPK signaling. In contrast, ZIKV promoted LD biogenesis, and inhibition of DGAT1 reduced both LD formation and viral replication, indicating a proviral role for LDs. Modulation of FA metabolism further revealed differential effects on ZIKV infection: saturated FA (palmitate) enhanced viral replication, whereas inhibition of FA oxidation with etomoxir reduced infection. Conversely, unsaturated FAs (oleate and linoleate) suppressed viral replication, in part by impairing viral binding and entry. Collectively, these findings show that ZIKV reshapes host metabolic pathways in TM by differentially engaging AMPK signaling, FA metabolism, and LD biogenesis to promote viral replication and spread in ocular tissue. Targeting these metabolic pathways may offer promising therapeutic avenues for preventing and/or treating ZIKV-associated ocular complications.

This study investigated the proteomic characteristics and biological functions of hypoxic exosomes derived from hypoxia-preconditioned feline adipose-derived mesenchymal stem cells (ADMSCs), aiming to reveal the remodeling effect of hypoxic preconditioning on the protein composition of exosomes derived from feline ADMSCs and its potential applications. CoCl2 was used to mimic a hypoxic environment for ADMSCs, and exosomes were isolated by differential ultracentrifugation. The physical properties of the exosomes were characterized by transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. Proteomic analysis revealed that hypoxic preconditioning significantly altered the exosomal proteomic profile, identifying 120 differentially expressed proteins (116 upregulated and 4 downregulated). Bioinformatic analysis indicated significant enrichment of key pathways including the hypoxia-inducible factor-1 (HIF-1) signaling pathway, adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, autophagy, and proteasome function. Gene ontology (GO) functional annotation demonstrated significant enrichment of biological processes such as metabolic processes, cell cycle regulation, and signal transduction in the hypoxia-preconditioned group. Kyoto encyclopedia of genes and genomes (KEGG) analysis further suggested potential biological functions through the regulation of pathways including the cell cycle and renin-angiotensin system. Notably, hypoxia-responsive proteins such as HMOX1 and TFRC were upregulated, while pathways related to the renin-angiotensin system were suppressed. This study systematically elucidates, for the first time, the remodeling effect of hypoxic preconditioning on the proteome of exosomes derived from feline ADMSCs, providing new molecular insights into exosome-mediated intercellular communication.

Glucose deprivation is a major metabolic stress that requires coordinated adaptive responses to maintain cellular homeostasis and survival, yet the role of tripartite motif-containing 24 (TRIM24) in this process remains unclear. To address this question, we generated CRISPR-Cas9-mediated TRIM24-knockout MCF-7 and HEK293 cell lines, performed targeted metabolomic profiling and aspartate assays, used 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), aminooxyacetic acid (AOA), aspartate supplementation, and glutamic-oxaloacetic transaminase 2 (GOT2) knockdown to probe AMPK signaling and aspartate metabolism, and examined starvation responses in constitutive Trim24 knockout mice on a C57BL/6 background. Loss of TRIM24 sensitized cells to glucose deprivation. Re-expression of TRIM24 partially restored cell viability under glucose deprivation in both MCF-7 and HEK293 cells. Under glucose-free conditions, TRIM24 deficiency was associated with impaired AMP-activated protein kinase (AMPK) pathway activation, increased intracellular aspartate accumulation, and altered ATP/AMP levels. Pharmacological reactivation of AMPK by AICAR improved the survival of TRIM24-deficient cells under glucose deprivation. Reducing intracellular aspartate by AOA treatment or GOT2 knockdown restored AMPK pathway activation and improved adaptation to glucose deprivation, whereas exogenous aspartate suppressed AMPK signaling and increased ATP/AMP levels. In vivo, starvation of Trim24-deficient mice was associated with reduced AMPK pathway activation and increased aspartate levels. Together, these findings support a model in which TRIM24 contributes to adaptation to glucose deprivation and in which abnormal aspartate accumulation contributes to impaired AMPK pathway activation in TRIM24-deficient cells.

Cardiovascular disease continues to impose a substantial global health burden and arises from interconnected pathological processes, including oxidative injury, inflammatory signaling, endothelial dysfunction, metabolic imbalance, and progressive cardiac and vascular structural remodeling. Growing interest has therefore emerged in naturally derived compounds capable of influencing multiple disease pathways simultaneously. Pterostilbene, a dimethoxylated stilbene structurally related to resveratrol, has gained attention due to its enhanced lipophilicity and improved bioavailability. Recent experimental studies have investigated the cardiovascular effects of pterostilbene in both cellular systems and animal models. Evidence from in vitro studies indicates that this compound modulates key regulatory networks involved in cellular energy metabolism, redox homeostasis, endothelial signaling, and stress-associated cardiomyocyte injury. These actions involve pathways linked to 5' adenosine monophosphate-activated protein kinase and sirtuin-1 signaling, nitric oxide regulation, antioxidant responses, and ferroptosis-related mechanisms. Findings from in vivo investigations further demonstrate protective effects across multiple cardiovascular disease models, including pulmonary hypertension, pressure overload-associated cardiac remodeling, ischemic myocardial injury, toxin-induced cardiotoxicity, and metabolic or atherosclerotic vascular dysfunction. Improvements in functional, structural, and biochemical parameters have been reported in these experimental settings. Overall, current preclinical evidence suggests that pterostilbene may act as a multifunctional modulator of key processes involved in cardiovascular pathology. Although clinical evidence remains limited, the convergence of mechanistic and experimental findings highlights its potential as a multi-target cardiometabolic therapeutic candidate and provides a foundation for future translational and clinical investigation.

Metformin remains the first-line pharmacological therapy for type 2 diabetes mellitus (T2DM). While its glucose-lowering effects have primarily been attributed to peripheral actions, evidence indicates that it also crosses the blood-brain barrier (BBB) and can exert anti-diabetic effects from within the central nervous system (CNS). This focused review discusses metformin's central actions and how they might integrate with established peripheral mechanisms of glucose-lowering. We synthesized recent mechanistic studies conducted in murine models using systemic and intracerebroventricular metformin administration, brain-specific genetic loss- and gain-of-function approaches, neuronal activation mapping, electrophysiology, and pharmacological interrogation of autonomic and metabolic pathways. The evidence reviewed indicates that clinically relevant low concentrations of metformin in the brain engage a ventromedial hypothalamus (VMH)-steroidogenic factor 1 (SF1) neuron-Ras-proximate-1 (Rap1) signaling axis, which is essential for its glucose lowering action. Notably, metformin inhibits Rap1 in VMH SF1 neurons to reduce hyperglycemia. This central mechanism appears specific to metformin and is not shared by other approved antidiabetic agents. Current data also imply that the CNS effects of metformin operate in conjunction with peripheral pathways including hepatic AMP-activated protein kinase (AMPK) signaling and gut-derived glucagon-like peptide-1 (GLP-1) secretion, to produce its overall metabolic effect. Collectively, these findings support a model in which metformin lowers glucose through an orchestrated integration of a central Rap-1 dependent mechanism and peripheral metabolic actions. Additionally, the recognition of a central component to metformin's pharmacology expands the mechanistic framework of this cornerstone therapy and may inform future therapeutic strategies targeting integrated brain-metabolic pathways in T2DM.