Search Results (4,236)

In this paper, we review the literature regarding metformin’s action on blood lipid concentrations in metformin-treated diabetic patients. Published data indicate that metformin reduces serum total cholesterol (T-C), LDL-cholesterol (LDL-C) and triacylglycerol (TAG) concentrations and raises serum HDL-cholesterol (HDL-C) concentrations in diabetic patients. The beneficial effect of metformin on serum lipid profiles in diabetic patients can result from (a) its action on AMP-activated protein kinase, which inhibits lipogenesis and cholesterol synthesis and stimulates fatty acid oxidation; (b) decreased plasma TAG concentrations, via promoting VLDL-TAG clearance by brown adipose tissue; (c) the inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2) gene expression, affecting lipid profile in diabetic patients; (d) the inhibition of the expression of genes encoding proprotein convertase subtilisin/kexin 9 (PCSK9) and lipogenic enzymes; (e) the downregulation of carbohydrate-response element-binding protein (ChREBP), which affects liver TAG and cholesterol synthesis from acetate formed by gut microbiota; (f) the inhibition of angiopoietin-like 3 protein (ANGPTL3) gene expression, and consequent effects on plasma TAG concentrations; (g) the activation of AMPK, which inhibits LXRα activity; and (h) reverse cholesterol transport. In conclusion, one can assume that beyond its primary antihyperglycemic effect, metformin exerts pleiotropic effects that modulate lipid metabolism and blood lipid profile in T2D patients. These beneficial effects of metformin on blood lipid profile may play a role in the reduction in cardiovascular risk in diabetic patients. Full article

Epidermal hyperinnervation is a major cause of intractable itch in barrier dysfunction conditions such as atopic dermatitis. Keratinocyte-derived semaphorin 3A (Sema3A) suppresses epidermal hyperinnervation, but its expression is markedly reduced in barrier-disrupted skin. Although konjac ceramide (kCer) has been reported to act as a Sema3A-like ligand, the mechanisms by which it regulates Sema3A expression in keratinocytes remain unclear. Normal human epidermal keratinocytes (NHEKs) were treated with kCer, konjac glucosylceramide (kGlcCer), or C24 ceramide. Sema3A mRNA and protein levels were assessed by quantitative real-time PCR and enzyme-linked immunosorbent assay, respectively. The involvement of intracellular signaling was examined using mitogen-activated protein kinase (MAPK) inhibitors, activator protein-1 (AP-1) inhibitors, retinoic acid-related orphan receptor alpha (RORα) inverse agonists, and siRNAs targeting c-Jun, c-Fos, and RORα. kCer induced Sema3A expression in NHEKs more potently than kGlcCer or C24 ceramide and promoted Sema3A protein secretion. Pharmacological inhibition or genetic knockdown of MEK1/2, JNK, AP-1 components, or RORα significantly attenuated kCer-induced Sema3A expression, indicating involvement of the MAPK/AP-1 signaling axis and RORα. kCer upregulates Sema3A expression in human keratinocytes through MAPK/AP-1 signaling and RORα, suggesting it may represent a promising antipruritic agent for epidermal hyperinnervation associated with skin barrier dysfunction. Full article

Background/Objectives: Circulating platelets mediate physiological hemostasis and are implicated in pathological thrombosis, which can cause vascular occlusion, leading to heart attacks or strokes. Costunolide is a sesquiterpene lactone extracted from Saussurea lappa. Although this lactone has multiple biological effects, including anti-inflammatory and antioxidant effects, that help slow the progression of atherosclerosis, its influence on platelet activation remains unclear. In this study, we examined the potential antiplatelet and antithrombotic effects of costunolide. Methods: We used platelet aggregation, flow cytometry, and Western blot analysis to examine its in vitro antiplatelet effects. Results: Our results indicated that costunolide inhibited platelet aggregation induced by collagen, but not by thrombin or the thromboxane A₂ analog U46619, suggesting that costunolide selectively inhibits collagen-induced platelet activation. Additionally, costunolide blocked collagen-mediated granule release, calcium mobilization, and glycoprotein IIb/IIIa (GPIIb/IIIa) activation. Costunolide also inhibited phospholipase Cγ2 (PLCγ2), pleckstrin (a downstream target of protein kinase C), Akt, and mitogen-activated protein kinase. Moreover, it prevented collagen/epinephrine-induced pulmonary thrombosis and increased the survival rate of mice. Furthermore, costunolide delayed thrombus formation in the mesenteric vessels while it did not significantly affect hemostasis, suggesting it exhibits antithrombotic activity without bleeding tendency. These findings indicate that costunolide can block PLCγ2-PKC, Akt, and MAPK signaling pathways and subsequent granule release, calcium mobilization, and GPIIb/IIIa activation, eventually impeding platelet activation, platelet aggregation, and thrombus formation. Conclusions: In conclusion, besides its multiple biological activities that are beneficial for slowing the progression of atherosclerosis, we also demonstrated the antiplatelet and antithrombotic activities of costunolide. These effects highlight the therapeutic potential of costunolide in the treatment of patients with cardiovascular disease, particularly stroke and heart attack. Full article

Adenosine has emerged as a central metabolic signal linking cellular stress to systemic physiological adaptation. Under conditions such as hypoxia, ischemia, inflammation, and tissue injury, extracellular adenosine triphosphate (eATP) released from stressed cells is sequentially metabolized by the ectonucleotidases CD39 and CD73, generating adenosine that accumulates in the extracellular microenvironment. This stress-responsive nucleoside activates four G-protein-coupled receptors (A1, A2A, A2B, and A3), triggering intracellular signaling networks including the cyclic adenosine monophosphate–protein kinase A (cAMP–PKA), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase–protein kinase B (PI3K–Akt), and hypoxia-inducible factor-1 alpha (HIF-1α) pathways. Through these integrated mechanisms, adenosine orchestrates diverse physiological processes such as vascular regulation, metabolic adaptation, immune modulation, and cellular survival. In the cardiovascular system, adenosine promotes coronary vasodilation and ischemic preconditioning, limiting reperfusion injury. In pulmonary tissues, it mediates acute anti-inflammatory responses but may also drive chronic fibrotic remodeling. Within the central nervous system, adenosine functions as a neuromodulator regulating neuronal excitability, sleep–wake homeostasis, and neuroprotection. In the tumor microenvironment, hypoxia-driven adenosine accumulation suppresses cytotoxic T cell and natural killer activity, facilitating immune evasion and tumor progression. Collectively, adenosine signaling represents a central integrative network that links metabolic stress sensing to coordinated cellular adaptation while simultaneously emerging as a clinically actionable therapeutic target across cardiovascular, inflammatory, neurological, and oncological diseases. Full article

Background: Baeckea frutescens L. (BF) has been reported as a potential natural source for skin-whitening agents. However, its antimelanogenic activity and mechanisms remain unclear. Methods: The antimelanogenic effects of BF were evaluated in α-melanocyte-stimulating hormone (α-MSH)-stimulated B16F10 cells and in zebrafish embryos. Cell viability, intracellular tyrosinase activity and melanin content were measured. Western blot (WB) analysis was used to examine melanogenesis-related proteins. Network pharmacology and molecular docking were performed to predict potential targets and interactions of BF-derived metabolites. Results: The ethanolic extract of BF reduced intracellular tyrosinase activity and melanin content in cells without cytotoxicity. Western blot analysis showed decreased expression of microphthalmia-associated transcription factor (MITF) and its downstream melanogenic enzymes, including tyrosinase (TYR), tyrosinase-related protein-1 (TRP-1), and dopachrome tautomerase (DCT). In addition, BF reduced phosphorylation of protein kinase A (PKA), cAMP responsive element-binding protein (CREB) and extracellular signal-regulated kinase (ERK), suggesting potential suppression of PKA/CREB and ERK signaling pathways. These regulatory effects may contribute to MITF downregulation and subsequent inhibition of melanogenesis. BF reduced melanin accumulation in zebrafish embryos. Network pharmacology and molecular docking analyses further suggested that BF-derived metabolites, particularly bayogenin, may interact with multiple melanogenesis-related targets. Conclusions: BF may inhibit melanogenesis through coordinated modulation of multiple signaling pathways and may represent a promising skin-whitening candidate. Full article

Maize (Zea mays L.), a typical thermophilic crop originating from tropical regions, exhibits an inherent sensitivity to low-temperature stress. Cold stress severely restricts maize seed germination, seedling growth, the physiological metabolism, and the final grain yield, which greatly limits its geographical cultivation range and sustainable industrial development. Elucidating the molecular regulatory mechanisms underlying maize cold tolerance and excavating cold-resistant functional genes are essential for the molecular breeding of cold-tolerant maize varieties and expanding maize planting areas in high-latitude and low-temperature-prone regions. In this study, using the strongly cold-tolerant maize inbred line B144 as the experimental material, we cloned the ZmMAPKKKA gene (NCBI accession: LOC103651289) and systematically screened and verified its cold-stress-specific interacting proteins via multiple molecular biological assays. The full-length coding sequence (CDS) of ZmMAPKKKA is 1134 bp, encoding a 377-amino-acid protein with a predicted molecular weight of 40.37 kDa. The quantitative real-time PCR (qRT-PCR) results demonstrated that the ZmMAPKKKA expression was significantly upregulated by 16.56-fold in maize roots after 12 h of low-temperature treatment, indicating a tissue-specific and robust cold response in root tissues. A total of 25 interacting proteins were identified through yeast two-hybrid screening, among which three stress-responsive proteins, including a protein kinase (LOC100286253), a protein phosphatase 2C (PP2C) (LOC542176), and a NAC transcription factor (LOC118474710), were selected for subsequent verification. The Pull-Down, Co-immunoprecipitation (Co-IP), and bimolecular fluorescence complementation (BiFC) assays consistently confirmed that ZmMAPKKKA specifically interacts with these three proteins both in vitro and in vivo under cold stress conditions. This study is the first to construct a ZmMAPKKKA-centered protein interaction module in the maize mitogen-activated protein kinase (MAPK) cascade under cold stress, establishing a novel kinase–phosphatase–transcription factor regulatory cascade that improves the current understanding of cold signal transduction mechanisms in maize. Homologous genes of ZmMAPKKKA in gramineous crops including rice (Oryza sativa) and sorghum (Sorghum bicolor) have been proven to participate in diverse abiotic stress responses, suggesting the conserved functional roles of MAPKKK family genes across gramineous species. Collectively, our findings provide comprehensive insights into the molecular mechanism of the maize MAPK signaling pathway mediating cold stress adaptation and supply valuable functional gene resources for cold-tolerant maize germplasm innovation and molecular breeding. Full article

Objectives: The purpose of the present study was to examine the acute effects on hematological, inflammatory, cellular, muscular, myocardial, liver, biliary, and humoral immunity biomarkers during and after a 12-h track ultra-marathon event. Methods: Twelve healthy male ultra-marathon runners completed the race and all measurements, including venous blood sampling performed before the race (PRE), at 6 h during the race (MID), and immediately after finishing (POST). Results: White blood cells, neutrophils, monocytes, basophils, and platelets increased at 6 h (MID) and remained elevated after the finish (POST), while eosinophils and lymphocytes decreased at mid-race and remained suppressed until post-race. The immunoglobulin G and C-reactive protein increased post-race compared to pre- and mid-race values, while lactate dehydrogenase and interleukin-6 increased at mid-race, with no further change until post-race. Creatine kinase, creatine kinase-MB, high-sensitivity cardiac troponin I, aspartate aminotransferase, and alanine aminotransferase significantly increased mid-race and showed a further significant increase post-race. Significant correlations were found between total distance covered and the percentage of PRE-MID difference of interleukin-6 and the percentage of PRE-POST difference of interleukin-6 and lactate dehydrogenase. Conclusions: The results of the present study indicate that participation in a 12-h track ultra-marathon is associated with marked exercise-induced alterations in multiple hematological and biochemical biomarkers, with several responses already evident at mid-race (6 h). Full article

The direct involvement of the phosphatidylinositol 3-kinase (PI3K)/serine threonine kinase (AKT) signaling pathway in the alleviation of the heat stress (HS)-induced damage to the integrity and barrier function of broiler jejunal organoids (JOs) by supplemental zinc (Zn) has not been confirmed. To verify it, two experiments were conducted in the present study. In experiment 1, the optimal concentrations of PI3K/AKT inhibitor (PI3K-IN-1) or agonist (YS-49) were screened. In experiment 2, the role of PI3K/AKT in Zn alleviation of HS-induced damage to JOs was evaluated with three JO types as control groups under baseline incubation temperature (40 °C) plus a 3 (JOs types) × 3 (Zn sources) factorial design under high temperature (44 °C). The results showed that the optimal concentrations of the PI3K-IN-1 and YS-49 for effectively inhibiting and promoting (p < 0.001) phosphorylation of PI3K and AKT were 16 μmol/L and 9 μmol/L, respectively. Adding Zn, especially Zn proteinate with moderate chelation strength (Zn-Prot M), alleviated (p < 0.001) the HS-induced increases in diamine oxidase content and lactate dehydrogenase activity in the media and the HS-induced decreases in JOs budding percentage, proportions of 5-ethynyl-2′-deoxyuridine and proliferating cell nuclear antigen positive cells, and the phosphorylation of PI3K and AKT. PI3K/AKT inhibition or activation reduced or enhanced (p < 0.05) the above alleviating effect of Zn, especially Zn-Prot M. These results indicate that the PI3K/AKT signaling pathway mediated the alleviation of HS-induced damage to integrity and barrier function of broiler JOs by supplemental Zn, particularly Zn-Prot M via promotion of cell proliferation. Full article

Background: Procalcitonin (PCT) is widely used as a biomarker of bacterial infection, but it may also increase in non-infectious inflammatory states. This study investigated the association of PCT with muscle injury severity and renal dysfunction in patients with non-traumatic rhabdomyolysis. Methods: We prospectively enrolled 39 adults with non-traumatic rhabdomyolysis (n = 39). Admission and longitudinal laboratory data included creatine kinase (CK), myoglobin, PCT, C-reactive protein (CRP), creatinine, and urea. Associations were assessed using Spearman correlation analysis with false-discovery-rate correction for multiple comparisons. Independent predictors of admission PCT were evaluated using linear regression with PCT (log10) as the dependent variable. Longitudinal dynamics were analyzed using linear mixed-effects models and a generalized mixed-effects sensitivity model. Results: At admission, after false-discovery-rate correction, PCT remained positively correlated with creatinine, CK, urea, and CRP; the weaker correlation with myoglobin did not remain significant after correction. In the primary admission model, both creatinine (log10) and CK (log10) were independently associated with PCT (log10), whereas infection status was not. In the broader sensitivity model, only creatinine (log10) remained significant. Longitudinal analyses showed that CK (log10) remained independently associated with PCT over time, including in the gamma mixed-effects sensitivity model; in that model, infection status was not independently associated with PCT. Conclusions: In this exploratory single-centre cohort of patients with predominantly intoxication- or immobilization-related “found-down” non-traumatic rhabdomyolysis, PCT elevation was associated with markers of muscle injury and renal dysfunction. Infection status was not independently associated with PCT in the fitted models; however, the modest sample size means that smaller infection-related effects cannot be excluded. These findings should therefore be interpreted cautiously and require confirmation in larger, more etiologically diverse rhabdomyolysis cohorts. Full article

Isovitexin (ISOV) is an active component identified in the traditional Tibetan medicine Tsantan Sumtang, which is commonly used for treating myocardial ischemia. Although previous studies have suggested the protective effect of ISOV on cardiomyocytes, the in vivo anti-ischemic efficacy and underlying mechanisms of ISOV remain unclear. This study aimed to systematically evaluate the therapeutic effects of ISOV on myocardial ischemia in rats and to elucidate its molecular mechanism of action. An acute myocardial infarction model was established in rats by ligating the left anterior descending branch (LADL) of the coronary artery. The protective effects of ISOV were assessed by measuring infarct size, serum cardiac injury biomarkers, and oxidative stress levels. Chemical proteomics using photoaffinity magnetic beads was employed to identify potential target proteins of ISOV. Molecular docking, pull-down western blotting, and cellular thermal shift assay (CETSA) western blotting were applied to validate the interaction between ISOV and target. Knockdown of the target was used to verify the mechanism of ISOV on anti-myocardial ischemia effect. ISOV treatment significantly reduced myocardial infarct size, decreased serum levels of lactate dehydrogenase (LDH), creatine kinase isoenzymes (CK-MB), malondialdehyde (MDA), and enhanced superoxide dismutase (SOD) activity in myocardial ischemia rats. Furthermore, ISOV improved mitochondrial function, as evidenced by increased ATP content and enhanced activities of mitochondrial complexes I and IV. Chemical proteomics and bioinformatic analysis identified SLC25A4 as a direct target of ISOV. Molecular docking revealed a high-affinity binding (binding energy: −8.3 kcal/mol), which was further confirmed by pull-down assays and CETSA. In SLC25A4-knockdown H9c2 cells under hypoxic conditions, ISOV upregulated SLC25A4 expression, promoted the phosphorylation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) and upregulated the expression of proliferator-activated receptor gamma coactivator-1$\alpha$ (PGC-1$\alpha$). ISOV exerts cardioprotective effects against myocardial ischemia by directly binding to SLC25A4 and activating the AMPK/PGC-1$\alpha$ pathway, highlighting its potential as a therapeutic agent for myocardial ischemia. Full article

Cynodon dactylon (Bermuda grass) is a perennial medicinal grass widely distributed across tropical and subtropical regions and known for its antioxidant and anti-inflammatory properties. The present study aimed to identify bioactive metabolites from the leaves of C. dactylon and evaluate their potential interaction with PTEN-induced kinase 1 (PINK1), a crucial regulator of mitochondrial quality control implicated in neurodegenerative disorders, particularly Parkinson’s disease. GC–MS analysis identified a total of 95 phytochemicals, of which the top 20 metabolites were selected based on retention time and area percentage. These metabolites were subjected to virtual screening using PyRx, with ATP employed as the reference ligand. Among the screened metabolites, 5,8,11-eicosatrienoic acid was the high-affinity compound which predicted a binding affinity of −5.9 kcal/mol and forming two hydrogen bond interactions within the PINK1 active site. The docked complexes were further evaluated through a 100 ns molecular dynamics simulation in replicates that showed stable binding of the protein–ligand complex, as reflected by RMSD values, reduced residue fluctuations and stable radius of gyration and solvent-accessible surface area. These findings suggest that 5,8,11-eicosatrienoic acid from C. dactylon may act as a potential PINK1 modulator for Parkinson’s disease. Full article

Objectives: Langerhans cell sarcoma (LCS) is a very rare, highly malignant tumor that originates from Langerhans cells. The differential diagnosis of LCS and Langerhans cell histiocytosis (LCH) still faces limitations, and the molecular changes involved in LCS are unclear. Molecular biomarkers and immunophenotypes may help distinguish between LCS and LCH. In this manuscript, the pathological and molecular markers in LCS are explored. Methods: The expression patterns of ASPP1, ASPP2, and inhibitor of apoptosis-stimulating p53 protein (iASPP) were examined using the immunohistochemical method and immunofluorescence staining. Then, genetic features, such as B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E, K-ras, and ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), were assayed using the amplification refractory mutation system (ARMS) method. Finally, whole-exon sequencing of LCS was performed. Results: Immunohistochemically, in all samples of LCS, ASPP2 was detected in ovoid and elliptic tumor cells. In the case of LCH, ASPP2 was expressed not only in ovoid and elliptic cells but also in histiocytic cells. The expression of iASPP was observed in five cases LCS (5/6), and no positive reaction was observed in the case of LCH. No ASPP1 expression was observed in LCH and LCS. During triple-color immunofluorescence analysis, ASPP2 and iASPP were co-expressed on Langerin⁺ LCS tumor cells. No mutations of BRAF V600E, K-ras, or ROS1 were detected in LCH and LCS. No gene mutation or rearrangement was detected in LCS except for the MAP2K1 gene. The mutation site was nonsynonymous in 607 bp of MAP2K1, resulting in a change from base G to A; thus, the amino acid E changed to K at the 203 site (4/6, 66.67%). Conclusions: Combined detection of ASPP2 and iASPP in tissue samples may provide valuable markers to differentiate between LCH and LCS. The MAP2K1 variants c.607G > A is the first potential marker to be reported in LCS. Full article

Glucagon-like peptide (GLP)-1 receptor (GLP1R) agonists exert a multitude of beneficial cardiovascular effects beyond control of blood glucose levels and obesity reduction. GLP-1R is a G protein-coupled receptor (GPCR), coupling to adenylyl cyclase (AC)-stimulatory Gs proteins to raise cyclic 3′-5′-adenosine monophosphate (cAMP) levels in cells. cAMP exerts various effects mainly via protein kinase A (PKA) and Exchange protein directly activated by cAMP (Epac). Cardiac GLP-1R has been reported to induce atrial natriuretic peptide (ANP) secretion via Epac2, while ANP is known to inhibit aldosterone secretion from adrenocortical zona glomerulosa (AZG) cells. Herein, we tested the effects of the GLP-1R agonist liraglutide on ANP secretion in H9c2 cardiomyocytes and on angiotensin II (AngII)-induced aldosterone secretion. We also examined whether phosphodiesterase (PDE)-4 inhibition with roflumilast could potentiate liraglutide’s effects. We found that liraglutide stimulated ANP secretion from H9c2 cardiomyocytes, an effect potentiated by roflumilast but blocked by AC inhibition. Epac inhibition with ESI-09 also significantly reduced liraglutide-dependent ANP secretion in H9c2 cardiomyocytes. Moreover, application of medium from liraglutide-treated H9c2 cardiomyocytes, but not from control cardiomyocytes, led to suppression of AngII-dependent aldosterone secretion from H295R cells. This effect was blocked by cyclic guanosine monophosphate (cGMP)-dependent protein kinase inhibition (an effector of ANP) in H295R cells, while direct application of liraglutide to these cells failed to suppress AngII-induced aldosterone secretion. Again, aldosterone suppression was more potent when medium from liraglutide plus roflumilast-treated cardiomyocytes was applied to H295R cells. Taken together, these results suggest that roflumilast enhances the adrenocortical aldosterone suppression induced by GLP-1R agonists via cardiac GLP-1R/cAMP/Epac-dependent ANP secretion. Given the cardio-toxic effects of elevated aldosterone levels in the context of various heart diseases, such as post-myocardial infarction heart failure, combination of a GLP-1R agonist drug with a PDE4 inhibitor drug may be more advantageous than either agent alone in treatment of certain cardiovascular diseases. Full article

Diabetic peripheral neuropathy (DPN) is a common and debilitating complication of diabetes mellitus which affects individuals with both type 1 and type 2 diabetes mellitus (T2DM), presenting with sensory loss, pain, and progressive nerve dysfunction. DPN pathogenesis is multifactorial: chronic hyperglycemia activates the polyol, hexosamine, and protein kinase C (PKC) pathways, increases advanced glycation end-products, and drives oxidative stress, mitochondrial dysfunction, inflammation, and impaired neurotrophic signaling. In addition to hyperglycemia-driven mechanisms, dyslipidemia and microvascular insufficiency exacerbate neural ischemia and metabolic stress. Recent mechanistic, animal, and associative human studies further implicate amyloidogenic toxicity, particularly from human islet amyloid polypeptide (hIAPP), as a plausible contributory factor in peripheral nerve degeneration in T2DM, linking protein misfolding and aggregation to axonal damage and demyelination in DPN. Despite increased understanding of these mechanisms, current treatments remain mainly symptomatic. Emerging therapeutic strategies, including antioxidants, anti-inflammatory agents, modulators of mitochondrial function, amyloid oligomer modulators, neurotrophic enhancers, and regenerative approaches such as stem cells and gene-based therapies, offer potential to modify disease progression. The strength of evidence across these methods varies, ranging from mechanistic and animal studies to early human research and, in some cases, randomized clinical trials. Therefore, although several candidates show potential to alter the disease, few have demonstrated consistent benefits on objective measures of nerve structure or function in large clinical trials. This review summarizes the key mechanisms driving DPN in T2DM and highlights promising therapeutic innovations poised for clinical translation. Full article

Background: Research indicates that hepatic gluconeogenesis mediates metabolic coupling between the liver and muscles via the Cori cycle and participates in liver–brain axis communication through its metabolic products and regulatory networks, thereby linking it to the pathogenesis of depression. Together, these mechanisms form the molecular basis for the antidepressant effects of exercise-regulated hepatic gluconeogenesis. Regular exercise promotes skeletal muscle contraction, causing the muscles to release more lactate into the circulatory system. Lactate acts as a substrate for gluconeogenesis and activates downstream signaling pathways, thereby enhancing the gluconeogenic response. During exercise, glycogenolysis directly provides energy, while lactate produced by glycolysis enters the liver via the Cori cycle to serve as a substrate for gluconeogenesis. By maintaining blood glucose homeostasis, this process ensures a stable energy supply to the brain, thereby improving cognitive and emotional functions. This study aims to elucidate how key substrates, regulatory factors, and rate-limiting enzymes involved in hepatic gluconeogenesis and exercise influence brain energy supply, cognitive function, and emotional regulation during depression. It seeks to identify the potential targets and mechanisms through which exercise exerts its antidepressant effects via hepatic gluconeogenesis, with the goal of providing a theoretical foundation for research into the mechanisms of depression and for clinical exercise interventions. Methods: This review conducted a comprehensive search of the recent literature on exercise, hepatic gluconeogenesis, and depression in major domestic and international databases. Adopting an interdisciplinary approach that integrates hepatic gluconeogenesis and exercise, it synthesizes existing evidence to explore the metabolic mechanisms by which exercise improves depression through the regulation of hepatic gluconeogenesis pathways. Results: Research has found that exercise may modulate hepatic gluconeogenic substrates and regulate the expression of cAMP-responsive element-binding protein in states of depression, regulatory factors such as liver kinase B1, forkhead box protein 01, hepatocyte nuclear factor 4 alpha, and peroxisome proliferator activated receptor gamma co activator factor 1 alpha are used to affect key rate limiting enzymes of hepatic gluconeogenesis, such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, enhance hepatic gluconeogenesis processes, maintain blood glucose homeostasis, ensure brain energy supply, and improve depression. Conclusions: Exercise intervention targeting hepatic gluconeogenesis may be a potential therapeutic strategy for depression. Full article