Search Results (1,119)

Caffeine (CAF) is a widely consumed psychostimulant known to modulate adenosine receptors and neurotransmitter systems, although its effects in invertebrates remain poorly understood. Environmentally relevant concentrations (5, 30, and 50 µg/L) are associated with altered behavior, including locomotion, exploration, and feeding, in the freshwater gastropod Physella acuta. This study examined molecular responses underlying these effects. Adult snails were exposed to CAF for 24 h and 7 days. Gene expression related to the nervous system and stress pathways was analyzed by RT-PCR, including A1AR, ADORA2B, AChE, GLRA2, DRD2, RYR, HSD11β, HSP70, SLC6A2, and SLC6A1. After 24 h, exposure to 50 µg/L CAF altered A1AR expression and caused downregulation of AChE, GLRA2, and DRD2, associated with observed behavioral changes. A1AR upregulation may indicate compensatory adjustment in adenosine signaling. After 7 days, A1AR remained upregulated, while genes linked to inhibitory neurotransmission showed partial recovery. Increased expression of genes involved in dopamine regulation and steroid metabolism suggested physiological adaptation. Overall, CAF induced dose- and time-dependent molecular responses in P. acuta, linking neurochemical disruption with behavioral changes and highlighting its ecological risk as an emerging freshwater contaminant. Full article

Caffeine is the most widely used psychoactive compound. In the brain, caffeine acts as a competitive, non-selective adenosine receptor antagonist of A₁ and A_2A, both known to modulate long-term potentiation (LTP), the cellular basis of learning and memory. But the effects of caffeine on synaptic function and plasticity cannot be reduced to a single inhibitory or facilitatory action. In the CA1 area of the hippocampus, low-micromolar caffeine has been reported to attenuate LTP, yet it remains unclear whether this action extends equally to other plasticity-related responses, including EPSP–spike coupling and paired-pulse responses. Here, we studied the effect of 30 μM caffeine on the field excitatory postsynaptic potentials (fEPSPs) and LTP evoked by Schaffer collateral stimulation in the CA1 region in mouse hippocampal slices. We compared theta-burst-induced long-term fEPSP potentiation, EPSP–spike (E-S) potentiation, input–output relationships, and paired-pulse responses after short (three burst-TBS3) and long (ten burst-TBS10) theta-burst stimulation. Caffeine attenuated long-term fEPSP potentiation induced by the longer theta-burst protocol and reduced the accompanying increase in population spike amplitude. In contrast, E-S potentiation induced by the shorter theta-burst protocol was preserved under caffeine exposure. Input–output analysis further showed that caffeine prevented the increase in population spike amplitude accompanying the development of long-term fEPSP potentiation, but did not prevent the population spike response changes associated with E-S potentiation. Caffeine also reduced paired-pulse deviations from 100%, most clearly for population spike amplitude, and this effect persisted after both the theta-burst protocols. Thus, 30 μM caffeine did not simply suppress CA1 plasticity-related responses, but distinguished TBS10-induced synaptic fEPSP potentiation from TBS3-induced EPSP–spike potentiation. These findings identify EPSP–spike coupling as a caffeine-preserved CA1 plasticity-related response and provide a basis for future receptor-selective and behavioral testing. Full article

Background/Objectives: Promoting white adipose tissue (WAT) browning into thermogenic beige adipocytes is a promising anti-obesity strategy. Yanggyeoksanhwa-tang (YST) has been used traditionally to alleviate obesity-related conditions. Catalpol and rhoifolin are major bioactive components of Rehmannia glutinosa (Gaertn.) and Lonicera japonica (Thunb.) with known metabolic or anti-inflammatory effects. However, their direct roles in adipocyte browning and the mechanisms via β3-adrenergic receptor (β3-AR) signaling are not well defined, and this study addresses this gap. Methods: To evaluate browning potential, 3T3-L1 adipocytes were treated with catalpol and rhoifolin during differentiation. The expression of browning markers and lipid metabolism or catabolism transcription factors was analyzed using Western blotting and quantitative real-time polymerase chain reaction. The involvement of the β3-AR and adenosine monophosphate–activated protein kinase (AMPK) signaling pathways was further validated using specific agonists and antagonists. Results: Both compound treatments significantly upregulated beige-specific (Cd137, Cited, Tbx1, Cidea, Fgf21, Tmem26) and mitochondrial biogenesis markers (Cox4, Nrf1, Tfam), accompanied by a marked increase in thermogenic markers (UCP1, PGC-1α, Prdm16). Concurrently, lipolysis-related genes such as Atgl, Hsl, and Plin1 were elevated, while lipogenesis targets (Fasn, Lpl, Srebf1, Acaca) were downregulated through activation of the β3-AR signaling pathway. Conclusions: These findings suggest that catalpol and rhoifolin, key phytochemicals of YST, promote WAT browning and lipolysis. Our findings indicate that these compounds induce browning and modulate metabolism via the β3-AR pathway. These results serve as a cornerstone for natural anti-obesity therapy, pending further validation in vivo and clinical studies. 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: Metabolic syndrome is characterized by dysregulated glucose metabolism and is a major risk factor for type 2 diabetes mellitus and cardiovascular disease. Although glucose-lowering therapies such as glucagon-like peptide-1 receptor (GLP-1R) agonists are effective, their use may be limited by cost, administration route, side effects and tolerability. Bergamot (Citrus bergamia Risso et Poiteau) extract, rich in flavanones, has shown favorable metabolic effects in clinical studies, although its mechanisms of action remain insufficiently defined. This study aimed to investigate the potential glucose-modulating mechanisms of a standardized phospholipid-formulated bergamot extract (BP) (Vazguard™) in vitro. Methods: GLP-1R activation was assessed in a U2OS cell line expressing cyclic adenosine monophosphate (cAMP)-sensitive Nomad Biosensors™. Dipeptidyl peptidase-4 (DPP4) activity was evaluated using a cell-free enzymatic assay, while Glucose transporter type 4 (GLUT4)-mediated glucose uptake was assessed in CHO-K1 cells stably expressing human GLUT4 using an adenosine triphosphate (ATP)-based readout. Cytotoxicity was also using lactate dehydrogenase (LDH), MTT, and nuclei count assays. Results: BP exhibited a dose-dependent (0.31–5 mg/mL) increase in cAMP biosensor fluorescence, consistent with GLP-1R-associated signaling and a maximal response of approximately 60% relative to the positive control (GLP-1R agonist II). No cytotoxic effects were observed. In contrast, BP showed no inhibitory effect on DPP4 activity and did not alter GLUT4-mediated glucose uptake under the experimental conditions tested. Conclusions: These findings provide novel mechanistic evidence that phospholipid-formulated bergamot extract suggests a possible involvement in GLP-1R-associated signaling in vitro, without detectable effects on DPP4 or GLUT4 pathways under the conditions tested. This suggests a mechanism consistent with weak agonist or allosteric modulation of GLP-1R and supports further investigation of bergamot formulated with phospholipids as potential natural adjuncts in metabolic health management. Full article

Polydeoxyribonucleotide (PDRN) activates the adenosine A2A receptor (A2AR), triggering anti-inflammatory signaling and providing essential nucleotides for the salvage pathway, thereby helping bypass metabolic bottlenecks and promoting tissue repair. Combining PDRN with biochemical agents and physical stimuli represents a significant shift in medical treatment, moving from monotherapy to an integrated, multi-target regenerative approach. These combinatorial strategies effectively address the limitations of PDRN, such as its rapid degradation and diffusion, by simultaneously meeting the structural, metabolic, and signaling needs of injured tissues. The mechanism of action for PDRN involves a synergistic effect with hyaluronic acid, amplification of growth factors (e.g., Platelet-Rich Plasma (PRP), Epidermal Growth Factor (EGF), Platelet-Derived Growth Factor (PDGF)), and enhancements from extracorporeal shockwave therapy (ESWT) and lasers. This results in a notable acceleration of the repair process for chronic wounds, musculoskeletal disorders, and neurological injuries. As intelligent delivery systems like responsive hydrogels and sustainable L-PDRN production continue to advance, these synergistic protocols are poised to redefine global standards of care in regenerative medicine and esthetic dermatology. Future clinical success will hinge on the standardization of sequence-specific protocols and large-scale validation to ensure long-term safety and efficacy. Full article

Objective: Peripheral arterial occlusive disease (PAOD) is characterized by impaired tissue perfusion, chronic ischemia, and increased platelet reactivity. Hyperbaric oxygen therapy (HBOT) is used as adjunctive treatment in advanced PAOD, but its effect on platelet function remains insufficiently studied. This study examined the association between HBOT and platelet aggregation. Methods: This prospective observational study included 90 patients with Fontaine stage IV PAOD and chronic ulceration, assigned to an HBOT group (n = 60) or waiting-list control group (n = 30). Patients were predominantly male; mean age was 66.82 ± 9.42 years in the study group and 63.00 ± 8.31 years in controls, and diabetes mellitus was present in 55.0% and 63.3%, respectively. Prior revascularization included open surgery in 33.3% and 30.0%, endovascular treatment in 36.7% and 43.3%, and no option for revascularization in 30.0% and 26.7%, respectively. HBOT was administered over 4 weeks (20 sessions, 2.0–2.5 ATA). Platelet aggregation was measured by impedance aggregometry using arachidonic-acid-induced aggregation (ASPI), adenosine-diphosphate-induced aggregation (ADP), and thrombin-receptor-activating peptide-induced aggregation (TRAP) agonists. Changes were analyzed using generalized estimating equation models adjusted for antiplatelet therapy, diabetes mellitus, smoking, and C-reactive protein (CRP). Results: Significant group × time interactions were observed for all platelet activation pathways, indicating greater reductions in the HBOT group than controls: ASPI (β = −290.5; p < 0.001), ADP (β = −243.6; p < 0.001), and TRAP (β = −330.9; p < 0.001). No significant change was observed in controls. HBOT was associated with reduced pain intensity, while CRP and platelet-to-lymphocyte ratio (PLR) remained stable. Ulcer size showed no significant change after 4 weeks. Conclusions: In patients with PAOD, HBOT was associated with reduced platelet reactivity independent of antiplatelet therapy. Further randomized studies are needed to determine its clinical significance. 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

Introduction: Caffeine is a widely consumed adenosine receptor antagonist with well-documented effects on arousal and performance, but its time-resolved neurophysiological signature across stages of information processing remains fragmented across event-related potential (ERP) paradigms. Objectives: This systematic and mechanistic review aimed to (i) identify and catalog human ERP studies testing caffeine effects, (ii) synthesize findings by task domain and ERP component family, and (iii) evaluate moderators including dose, timing, abstinence/withdrawal control, sleep status, and habitual use. Methods: Following PRISMA 2020 and PRISMA-S, we searched multiple databases (PubMed/MEDLINE, Embase, APA PsycINFO, Web of Science Core Collection, Scopus, IEEE Xplore, and Cochrane Central Register of Controlled Trials) from inception to 28 November 2025 and conducted a structured narrative synthesis using SWiM (Synthesis Without Meta-analysis, no prespecified quantitative pooling). Risk of bias was assessed using RoB-2 (Risk of Bias 2, including crossover extension) and ROBINS-I (Risk Of Bias In Nonrandomized Studies of Interventions). Of 761 records, 63 controlled human studies met the inclusion criteria. The evidence most consistently supported stage- and context-dependent modulation. Within the P3 family, target-related P3b/P300 latency was frequently shortened, or fatigue-related slowing was prevented, often without parallel increases in amplitude. P300 amplitude findings were mixed and context-dependent: amplitude was often unchanged in rested or low-demand paradigms, but increased or was restored when caffeine counteracted fatigue, sleep loss, sustained attention demands, or high workload. Preparatory activity (CNV/slow negativity) showed selective effects, while early sensory components were comparatively stable in many paradigms; higher doses (approximately 200–400 mg) were associated with weaker early auditory sensory gating in some studies. Conclusions: Across heterogeneous paradigms, caffeine was associated with context-dependent ERP changes rather than a uniform amplification of ERP amplitudes. The most consistent pattern was shorter or preserved latency of late positive ERP components, particularly in tasks requiring stimulus evaluation or target detection. In some fatigue, sleep deprivation, sustained attention, or high-demand paradigms, caffeine was also associated with larger or restored P300/P3b amplitudes. These findings are compatible with state-dependent changes in attentional engagement or stimulus evaluation, but mechanistic interpretation remains limited by heterogeneity in task paradigms, ERP definitions, dosing, abstinence procedures, and participant caffeine use profiles. Methodological heterogeneity, small samples, inconsistent control of habitual use and withdrawal, and the predominance of healthy young adult samples limit generalizability, particularly to children, older adults, clinical populations, and long-term high-dose caffeine users. Full article

Amino acids are essential nutrients for both tumor growth and immune cell function. Cancer cells actively deplete intracellular and extracellular amino acid pools, and limited amino acid availability in the tumor microenvironment (TME) reinforces immunosuppression. Mitochondria are not merely adenosine triphosphate-producing organelles. Amino acid metabolism within mitochondria contributes to tumor progression and influences immune cell fate and effector function. These effects are mediated through biosynthetic precursor generation for lipid, nucleotide, and polyamine synthesis, maintenance redox homeostasis through glutathione and NAD⁺ metabolism, and regulation of gene expression through aryl hydrocarbon receptor signaling. In this review, we discuss four major mitochondrial amino acid metabolic pathways: glutamine-driven anaplerosis, serine/glycine-dependent one-carbon metabolism, arginine–ornithine metabolism, and tryptophan–kynurenine metabolism. We examine how these pathways are rewired in cancer cells, how they influence immune cell function through direct or mitochondria-associated mechanisms, and how such metabolic reprogramming promotes tumor progression while impairing antitumor immunity. Finally, we consider therapeutic strategies to improve cancer immunotherapy by targeting amino acid metabolism, including mitochondrial metabolic enzymes. This review may help guide the development of more effective metabolic biomarkers and mitochondria-based therapeutic strategies for cancer immunotherapy. 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

Angelman syndrome (AS) is a neurodevelopmental disorder caused by the loss of maternal UBE3A expression, leading to disrupted proteostasis and synaptic dysfunction. Adenosine is a ubiquitous neuromodulator whose G protein-coupled receptors (ARs) regulate neuronal differentiation and neurite outgrowth during development. Here, we investigated AR signaling and their influence on survival–autophagy balance and neuronal morphology in an AS cellular model. Using SH-SY5Y cells with silenced UBE3A, we found that UBE3A loss markedly decreased A1AR, A2BAR, and A3AR protein levels while significantly increasing A2AR expression. Ligand affinity was preserved across genotypes, but A1AR and A2AAR desensitization kinetics were significantly slower in UBE3A-deficient cells. These effects were associated with reduced recruitment of G protein-coupled receptor kinase 2 (GRK2) to the plasma membrane and decreased GRK2–AR association in UBE3A-deficient cells, suggesting a possible contribution of altered GRK2 dynamics to prolonged AR signaling. Functionally, A1AR and A2AR agonists preferentially promoted survival of UBE3A-deficient cells and modulated the MDM2–p53 axis and autophagy markers; A1R stimulation also increased neurite density in UBE3A-deficient cells. Together, these results identify AR-level alterations and defective desensitization machinery in AS neuronal cells and link receptor changes to downstream proteostasis and morphological phenotypes relevant to AS pathophysiology. Full article

We showed recently that the adenosine system and nitric oxide (NO) can interact differently in the control of renal function in normoglycaemia (NG) versus streptozotocin-induced diabetes (DM). Herein, we investigated if this relationship is modulated by dietary betaine (Bet, food compound possessing antioxidant and anti-inflammatory properties), to examine if adenosine receptor signalling in NG and DM females is altered by chronic Bet supplementation. The effects of intravenous infusion of theophylline, non-selective adenosine receptor antagonist, were examined in anaesthetised Sprague–Dawley female rats, pretreated for 2 weeks with Bet alone or combined with 4-day NO synthesis blockade with L-NAME (Bet + L-NAME). Renal blood flow (RBF, ultrasound artery probe), perfusion of the cortex, outer (OM-BF) and inner medulla (IM-BF; laser-Doppler technique), and tissue NO signal (selective electrode) were determined along with renal excretion. Bet and Bet + L-NAME decreased baseline RBF irrespective of glycaemia, whereas Bet lowered (NG) or elevated (DM) basal OM-BF; Bet + L-NAME treatment abolished these effects. Baseline sodium excretion decreased after Bet and Bet + L-NAME in NG only. Bet modified theophylline effects: IM-BF was lowered in DM rats, while tissue NO changes shown in the control were modified: NO increased in NG and decreased in DM. In NG, these effects were abolished by Bet + L-NAME. Bet pretreatment did not alter diuresis, natriuresis and kaliuresis, but after Bet + L-NAME these parameters increased (NG) or decreased (DM). Dietary Bet has the potential to affect renal medullary blood circulation; however, the eventual effect depends on glycaemia. Bet can modify renal functional changes induced by the interplay of the adenosine and NO systems, both in rats with normoglycaemia and streptozotocin diabetes. Full article

Background/Objectives: Leprosy is a chronic infection caused by Mycobacterium leprae that, in addition to Schwann cells, macrophages, and adipocytes, also infects human peripheral blood monocytes and subverts their metabolism in its favor. Infection is marked by cholesterol and fatty acid accumulation in lipid droplets (LDs), and a reduction in mitochondrial membrane potential (Δψm). Previous studies showed that M. leprae downregulates adenosine receptor A_2A (A_2AR) expression in Schwann cells, while activation reduces LD accumulation and bacterial viability. Since A_2AR controls immunometabolic response, we investigated whether A_2AR signaling restrains M. leprae-driven reprogramming in monocytes. Methods: Peripheral blood mononuclear cells from healthy donors were enriched for monocytes and infected with M. leprae in the presence or absence of adenosinergic modulators (5′AMP, adenosine (ADO), A_2AR agonist CGS21680, the antagonist ZM241385, or A_2BR antagonist, MRS1754). We used flow cytometry, fluorescence microscopy, and RT-qPCR to evaluate purinergic components expression and bacillary viability. LDs and Δψm were measured by fluorescence microscopy, and extracellular levels of inosine (INO) and hypoxanthine (HPX) by LC-MS/MS. Results: The results show that infection increased CD39, ADA, A_2AR and A₃R expression, decreased ENT1, A₁R and A_2BR, and raised extracellular INO and HPX. In addition, 5′AMP, ADO and CGS21680 reversed infection-induced LD accumulation. CGS21680 also restored Δψm and decreased intracellular M. leprae viability. Conclusions: Our data suggest that M. leprae suppresses A_2AR signaling to favor its survival in monocytes, indicating that the extracellular ADO–A_2AR pathway may be a potential target to limit early M. leprae infection. Full article

Background and Objectives: Tamoxifen, a cornerstone selective estrogen receptor modulator in breast cancer therapy, is increasingly recognized to be associated with retinal toxicity characterized by mitochondrial dysfunction, oxidative stress, lipid peroxidation, and oxidative DNA injury. By targeting mitochondrial bioenergetic dysfunction and redox disequilibrium, adenosine triphosphate (ATP) emerges as a biologically plausible candidate for retinal cytoprotection. This study aimed to evaluate the protective effect of ATP against tamoxifen-induced retinal toxicity in a rat model. Materials and Methods: Twenty-four male albino Wistar rats were randomly assigned to four groups: healthy control (HG), ATP-alone (ATPG, 4 mg/kg, intraperitoneally), tamoxifen-alone (TAMG, 5 mg/kg, orally), and tamoxifen plus ATP-treated (ATAG; ATP, 4 mg/kg, intraperitoneally; tamoxifen, 5 mg/kg, orally). Treatments were administered once daily for 30 days. Oxidative stress markers (malondialdehyde, total glutathione), antioxidant enzyme activities (superoxide dismutase, catalase), and oxidative DNA damage (8-hydroxy-2′-deoxyguanosine) were assessed in ocular tissues. Retinal histopathological evaluation included hematoxylin–eosin staining with semiquantitative assessment of edema, vascular congestion, polymorphonuclear leukocyte infiltration, and cytoplasmic vacuolization, together with quantitative measurements of retinal layer thicknesses and ganglion cell layer (GCL) cell counts. Results: Tamoxifen administration induced marked oxidative stress, antioxidant depletion, and increased oxidative DNA damage in ocular tissues, accompanied by significant thickening of retinal layers, reduced GCL cell counts, and pronounced disruption of retinal architecture. By comparison, ATP co-administration significantly suppressed lipid peroxidation and restored antioxidant defenses, thereby reducing oxidative DNA damage and preserving retinal structural integrity, as reflected by partial normalization of retinal layer thicknesses, preservation of GCL cell counts, and the presence of only mild residual edema. Conclusions: These findings indicate that ATP attenuates tamoxifen-induced retinal toxicity by supporting mitochondrial energy balance and redox homeostasis. Accordingly, ATP administration may represent a promising protective approach for reducing retinal injury associated with long-term tamoxifen therapy. Full article