Chronic kidney disease and its complications, including renal fibrosis, diabetic nephropathy, and renal cell carcinoma represent a major global health burden with limited therapeutic options. Resveratrol, a naturally occurring polyphenol found in grapes and berries, has emerged as a promising therapeutic candidate due to its multifaceted biological activities. Extensive research demonstrates resveratrol's remarkable renoprotective properties across various renal pathologies. It effectively attenuates tissue scarring, mitigates diabetes-related kidney damage, inhibits cancer progression, and protects against drug-induced nephrotoxicity. These broad-spectrum benefits stem from its unique ability to simultaneously target oxidative stress, inflammation, angiogenesis, apoptosis, and cellular damage pathways. Clinical investigations have confirmed resveratrol's potential to improve renal function markers in patients, while advanced formulation strategies are enhancing its therapeutic effectiveness. The compound's excellent safety profile further supports its clinical translation potential. This comprehensive review evaluates the current evidence for the renoprotective effects of resveratrol, focusing on its mechanisms of action in kidney diseases.

Foam cell formation is a critical pathological process that contributes significantly to the development of atherosclerosis, influenced by processes such as vascular senescence and autophagy-lysosomal pathways. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) has recently received interest due to its role in foam cell formation, but its connection to senescence and autophagy are still not well defined. This research investigated the role of Nrf2 in modulating senescence and autophagy in foam cells using an model of THP-1-derived macrophage foam cells. The effect of siRNA-induced silencing of Nrf2 on intracellular lipids buildup, cholesterol efflux, and the activation of senescence and autophagy were analyzed. Our findings indicate that Nrf2 silencing reduced the formation of foam cells by lowering intracellular lipid accumulation and enhancing cholesterol efflux in THP-1 macrophages. Additionally, silencing of Nrf2 lead to a reduction in cellular senescence, reflected by reduced β-galactosidase activity and a decrease in the expression of senescence-associated secretory phenotype (SASP) markers (Matrix metalloproteinase-9 (MMP-9) and tumor necrosis factor (TNF-α)) expression. This is accompanied by activation of autophagy, as indicated by enhanced formation of autophagosome and LC3B expression. Furthermore, inhibiting the late stage of autophagy with hydroxychloroquine (HCQ) decreased cell viability, while early-stage autophagy inhibition using 3-Methyladenine (3-MA) had no significant effect. These results highlight the critical role of Nrf2 in controlling foam cell development, senescence, and autophagic processes, giving valuable insights into potential therapeutic targets for atherosclerosis.

Coffee is a widely consumed beverage that has been shown to have numerous health benefits including positive effects on neurological and psychological conditions including depression. Although positive benefits have been observed, some epidemiological studies have shown that with high consumption of caffeinated coffee, the risk of suicide increases significantly. Therefore, the aim of this study was to investigate the toxicity of key coffee constituents in neuronal models. The viability of SH-SY5Y neuroblastoma cells was evaluated after 24 h treatment with a range of concentrations (10 µM, 100 µM, and 1000 µM) of caffeine, caffeic acid (CA), chlorogenic acid (CGA), ferulic acid, pyrogallic acid (PA), and trigonelline. Furthermore, specific cell death pathways were investigated for their role in coffee constituent-induced toxicity. It was found that high concentrations (1000 μM) of CA, CGA, and PA were toxic toward undifferentiated SH-SY5Y neuroblastoma cells and caffeine, CA, CGA, and PA toward dibutyryl cyclic AMP differentiated SH-SY5Y neuroblastoma. After mechanisms were investigated cytotoxicity appeared to be due to reactive oxygen species (ROS)-induced apoptosis. This study has shown that high concentrations (1000 μM) of key constituents of coffee were toxic toward both undifferentiated and dibutyryl cyclic AMP differentiated SH-SY5Y cells.

Diquat is used in agriculture as an herbicide but poses significant health risks upon exposure. Current treatment for toxic exposures to diquat focuses on supportive care, and there is a need for better understanding of the molecular mechanisms underlying diquat-induced injury in order to develop more targeted antidotes. To this end, TGF-alpha transgenic mouse hepatocyte (TAMH) cells were exposed to various concentrations of diquat to determine toxicologically relevant concentrations followed by subsequent transcriptomic analysis. Data mining from the MicroArray Quality Control (MAQC)-II dataset, which was accessed through the Gene Expression Omnibus (GEO) was also leveraged during the gene network analysis. A median lethal concentration (LC) for diquat in the TAMH line was determined to be 18 μM, with significant cell death observed at 9 h. Microarray data identified 3578 significantly altered transcripts in the TAMH model and 6554 from the MAQC-II dataset, with notable overlap in gene expression changes. Pathway analysis using Database for Annotation, Visualization and Integrated Discovery (DAVID) highlighted MAPK signaling as playing a role during diquat-induced toxicity in both models, with 11 shared transcripts suggesting a conserved molecular response across rodent species. This study aimed to investigate the molecular mechanisms behind diquat-induced toxicity using TAMH cells and identified MAPK signaling pathway as involved. By demonstrating the utility of combining GEO and DAVID for pathway analysis, this study not only highlights potential therapeutic targets for diquat toxicity but also presents a broadly applicable, cost-effective strategy for toxicogenomic research.

Nanoplastics (NPs) are emerging as environmental pollutants with the capacity to penetrate biological barriers, distribute systemically, and cause toxicity to multiple organs. Although early studies have primarily focused on localized organ damage, growing evidence suggests that NPs exert broader biological effects by disrupting interorgan communication through established physiological axes. In this review, we examined NP-induced toxicity through seven critical organ-organ pathways, including the gut-liver, gut-brain, gut-endocrine, liver-kidney, hypothalamus-pituitary-gonadal (HPG), hypothalamus-pituitary-adrenal (HPA), and placenta-fetus. NPs initiate damage at primary exposure sites, such as the intestinal epithelium or hypothalamic neurons, which propagates to secondary organs through hormonal, immunologic, and metabolic signaling. Shared histopathological features, including epithelial or parenchymal degeneration, inflammatory infiltration, and fibrotic remodeling, are consistently observed across axis-linked tissues. Moreover, bidirectional feedback mechanisms within these axes amplify NP-induced dysfunction and promote system-wide pathology. The ability of NPs to cross the placental barrier, accumulate in fetal tissues, and disrupt organ development is of particular concern and suggesting a potential for transgenerational toxicity. Overall, this axis-based framework highlights NPs as systemic toxicants that compromise the integrity of interconnected biological systems. In addition to single-organ perspectives, this review proposes an integrative model for understanding the complex and often indirect effects of chronic NP exposure on organismal health.

Glioblastoma cells exhibit a pronounced dependence on glutamine uptake, primarily the alanine‑serine‑cysteine transporter 2, since its deletion prevents glioma growth, making this transporter an attractive therapeutic target. This study aimed to evaluate 6‑pentadecyl salicylic acid, a natural antineoplastic and immunomodulatory compound, for its ability to impair alanine‑serine‑cysteine transporter 2‑mediated glutamine transport and by these means reduce glioblastoma cells viability. Human U373MG glioma cells and primary chick cerebellar Bergmann glia (non‑malignant control) were exposed to increasing concentrations of 6SA for 24 h. Viability, measured by the MTT assay, declined in a dose‑dependent manner in U373MG cells while Bergmann glia remained largely unaffected ( < 0.001). L-[³H]-glutamine uptake assays revealed that 100 µM 6SA functioned as a potent inhibitor, increasing the Michaelis constant (K) more than four-fold (from 7.11 mM to 31.79 mM). This indicates a mixed-type or competitive inhibition mechanism that dramatically reduces the transporter's apparent affinity for glutamine and prevents saturation within the tested substrate range. Additionally, quantitative PCR showed a dose‑dependent down‑regulation of ASCT2 mRNA, suggesting post‑transcriptional control. Blind docking of 6SA onto the cryo‑EM ASCT2 structure identified nine peripheral cavities that could serve as allosteric sites, however, these predictions are computational and require experimental validation; binding to these sites would stabilize a low‑affinity transporter conformation, consistent with the kinetic data. Collectively, 6‑pentadecyl salicylic acid selectively impairs glutamine transport and viability in glioblastoma cells while sparing normal glial cells, supporting its potential as a lead compound for alanine‑serine‑cysteine transporter 2 ‑targeted glioma therapy.

Drug hepatotoxicity is one of the primary reasons for drug clinical trial failures and market withdrawals, with mitochondrial dysfunction being one of the mechanisms inducing drug hepatotoxicity. Manifestation of mitochondrial toxicity occurs when mitochondria are damaged or their functions are inhibited. This study introduces M3Hep, a novel multimodal framework that integrates SMILES, molecular graphs, and mitochondrial toxicity through a masking strategy to improve hepatotoxicity prediction. A total of 8,459 mitochondrial toxicity samples and 6,418 hepatotoxicity samples were collected for constructing the mitochondrial toxicity prediction model and M3Hep, respectively. To fully utilize the collected hepatotoxicity samples, this study developed a mitochondrial toxicity prediction model to predict mitochondrial toxicity for molecules without experimental mitochondrial toxicity data, achieving an AUC of 0.96 for the mitochondrial toxicity prediction model. The ablation study results of M3Hep indicate that incorporating mitochondrial toxicity enhances the performance of hepatotoxicity prediction models, further demonstrating the connection between mitochondrial toxicity and hepatotoxicity. M3Hep outperforms most baseline models across all metrics, with its AUC reaching up to 0.81. Moreover, in terms of the MCC metric, M3Hep surpasses all commonly used hepatotoxicity prediction tools collected, with a value of 0.49. In order to better understand the prediction mechanism of M3Hep, we conducted an interpretability analysis based on the GNNExplainer and SHAP methods.

Norfluoxetine (NFLU), a metabolite of the antidepressant fluoxetine, is a known persistent endocrine-disrupting chemical (EDC) detected in aquatic environments. This study applies the Coastal Biosensor for Endocrine Disruption (C-BED) transcriptomic tool to evaluate NFLU's effects on the marine mussel . After an experiment in which mussels were exposed to 500 ng/L NFLU for six days, gonads from both sexes were analyzed for C-BED gene expression. Significant sex-specific changes were observed in the expression of genes encoding caveolin 3 (CAV-3) serotonin receptor (SR) and membrane-bound transcription factor protease (MBTP). NFLU downregulated CAV-3, SR, and MBTP in male gonads but upregulated CAV-3 and SR in females, with the largest change being a 21-fold decrease in CAV-3 expression in males and a 14.6-fold increase in females. These findings demonstrate that C-BED biomarkers are sensitive to norfluoxetine, while revealing pronounced sex-specific differences that underscore their importance for biomonitoring and ecotoxicological risk assessment.

Asbestiform fibers and cleavage fragments of the same mineral have different origins, though distinguishing between samples of fibers and fragments is often complicated. This study aims to demonstrate an efficient method for distinguishing between samples of two commercial amphibole asbestos types (crocidolite and amosite) and their non-asbestiform varieties. For the study, 15 dimensional datasets were used. For classification, two metrics were used: the fraction of elongate mineral particles with 2.99log(length)-5.82log(width)-3.80 ≥ 0, and the Pearson Index, which is the linear correlation coefficient between log(width) and log(length) of elongate mineral particles in the set. The decision boundary of CriteriaParticlesFraction ≥ 0.34PearsonIndex + 0.35 was found to predict the correct habit for amphibole datasets with an average error rate of 0.4% (Cohen's Kappa statistics 0.992). Additionally, several quantitative characteristics were used that have been demonstrated to be predictive of mesothelioma potency factors of elongate particles. These include dimensional coefficient of carcinogenicity (DCC), found as 1 - exp(-A x Surface Area/(B x width +C)), EMPA (fraction of particles longer than 5 µm with diameter not higher than 0.15 µm), EMPB (fraction of particles longer than 5 µm with diameter not higher than 0.25 µm), and aerodynamic diameter of the particles. It was demonstrated that asbestiform and non-asbestiform datasets have significantly different dimensional parameters that can be related to dissimilar toxicological effects.

Nitrosamines are a broad class of chemical compounds that are generally produced when amine congeners react with nitrosating substances, occasionally with nitrites present. Tobacco smoke, processed foods, certain medications, and industrial environments are among the many places in the environment where these substances are present. Because of their strong genotoxic and mutagenic properties, -nitroso compounds-in particular, -nitrosamines-have sparked worries about world safety. This review emphasizes nitrosamines' chemical interactions, metabolism, carcinogenic processes, control, and risk assessment in order to aid in this knowledge. It will help researchers manage nitrosamine-induced toxicity and promote safer pharmaceutical goods, as well as molecular biologists, analytical scientists, formulation scientists, and others in the research and development industry. The review examines the function of enzymes in nitrosamine metabolism, their capacity for DNA damage and mutagenesis, and epidemiological data correlating nitrosamine exposure with stomach and esophageal malignancies.

Drug abuse screening is a public health and legal priority in the United Arab Emirates (UAE), where rapid and accurate detection is critical in workplaces, healthcare, and forensic settings. This study evaluates the diagnostic performance of the ACCU-TELL Multi 7 Drug Panel Cup Test (Urine) as a rapid screening tool for detecting seven commonly abused substances. A total of 228 urine samples from diverse clinical and occupational contexts were analyzed using the ACCU-TELL test and compared with the Atellica Immunoassay System. The test demonstrated high sensitivity (92.5%), specificity (92.6%), and an overall accuracy of 92.1%. The area under the ROC curve (AUC) was 0.926, confirming excellent diagnostic performance. The ACCU-TELL Cup Test offers practical advantages such as affordability, ease of use, and immediate results, making it suitable for high-throughput screening where timely decisions are essential. Its application is particularly relevant in the UAE, where drug violations carry significant legal consequences and early detection aids both preventive and rehabilitative interventions. These findings support the ACCU-TELL test as a reliable alternative to conventional lab-based methods for preliminary drug abuse screening in resource-limited or time-sensitive environments.

Chemical pollution threatens the balance, resilience and health of coastal ecosystems, and there is a need for relevant tools to monitor and assess the sensitivity of these vital ecosystems. The common periwinkle () is a key intertidal species of high ecological and biomonitoring relevance. This study aimed to develop a rapid toxicity test to evaluate behavioral responses of utilizing 3,4-dichloroaniline (3,4-DCA) as a model compound. The snails were exposed to five concentrations (0.4-15.9 mg/L) over a four-day period, followed by a two-day recovery period. Behavioral endpoints assessed included active suction, righting performance, and feeding response. The exposure resulted in a concentration-dependent decrease in active suction, with snails retracting into their shells, which significantly reduced their oxygen consumption, indicating avoidance behavior. Post-exposure recovery demonstrated impaired righting performance and feeding activity, where higher 3,4-DCA concentrations correlate with reduced responsiveness. Notably, even at the lowest exposure concentration, fewer than 20% of snails were able to right themselves within 24 h, underscoring this as a highly sensitive behavioral endpoint. Feeding assays using revealed dose-dependent reductions in feeding activity. In conclusion, our study illustrates that displays sensitive and quantifiable behavioral responses to chemical exposure, thereby reinforcing its potential as a non-model species for marine ecotoxicity testing.

Cardiovascular diseases are often driven by oxidative stress and endothelial dysfunction, particularly under heavy metal exposure such as HgCl. It disrupts NO signaling and RAS balance, impairing vascular function. L-arginine (LA) and tetrahydrobiopterin (BH) as essential regulators of eNOS, are potential therapeutic agents for restoring vascular reactivity.

Brominated flame retardants (BFRs) are ubiquitous and persistent environmental contaminants owing to their extensive use in consumer products. Although linked to various adverse health effects, the underlying molecular mechanisms remain complex. This review consolidates scientific evidence positioning mitochondria as a central target of BFR toxicity, unraveling the pathways that drive cellular damage. The analysis revealed that BFRs converge on the fundamental mechanisms of mitochondrial injury. They consistently impair bioenergetics by disrupting the electron transport chain and uncoupling oxidative phosphorylation, leading to ATP depletion and collapse of the mitochondrial membrane potential (ΔΨm). This energetic failure triggers a surge in reactive oxygen species, overwhelming antioxidant defenses, and causing severe oxidative damage. Beyond these common effects, this review highlights remarkable mechanistic plasticity. Tetrabromobisphenol A can induce distinct cell death programs, including apoptosis, necroptosis, and ferroptosis, depending on the cellular context of the study. Furthermore, BFR biotransformation can yield metabolites such as hydroxylated polybrominated diphenyl ethers (PBDEs) that exhibit significantly greater toxicity than their parent compounds. Finally, mitochondrial dysfunction is a central hub that orchestrates cellular damage by BFRs. This is critically highlighted by the replacement of BDE-209 with decabromodiphenyl ethane, a regrettable substitution, where the new compound shares similar mitotoxic mechanisms and has become a widespread pollutant. This underscores the urgent need for a paradigm shift toward mechanism-based risk assessment to prevent future cycles of hazardous chemical replacements and to guide the design of genuinely safer alternatives.

The potential of Trigonella foenum-graecum or fenugreek seed extract in alleviating chronic hyperglycemia is supported by scientific evidence. In addition to its role in optimizing the insulin signaling pathway, fenugreek extract can also prevent the generation of Advanced Glycation End products (AGE) by sequestration of reactive carbonyl groups involved in the formation of Schiff base with lysine and arginine residues of protein side chains. In the present work, a patented and standardized extract of Fenfuro was found to reduce AGE fluorescence by 75%, along with a corresponding decrease in Thioflavin T fluorescence of nearly 85%. It was determined that these significant spectral changes were due to a combined effect of the protein as well as non-protein part of the extract and not attributable to any single bioactive component. The precipitated protein from the extract itself showed Thio-T fluorescence and gave a single band around the 65 kD MW range. The non-protein supernatant, when incubated with the glycated protein, gave an enhanced AGE as well as Thio-T fluorescence thus negating any possibility of plant extract mediated quenching of fluorescence leading to false interpretations. 8-Anilinonaphthalene-1-sulfonic acid (ANS) fluorescence spectra indicated that the extract provided substantial protection against thermal denaturation.The results collectively provided significant insights for exploring newer avenues of fenugreek-based therapeutics for treating both diabetes and neurodegeneration.

Previous studies have identified associations between lead (Pb) exposure and the incidence of Alzheimer's disease (AD), yet the underlying mechanisms are still missing. This investigation verified the association between Pb exposure burden and AD risk in a small case-control study. Using a nontargeted quantification lipidomic assay, the role of 3034 lipid metabolites in the associations between Pb exposure and AD risk was also explored. The results showed that serum Pb levels in AD patients were significantly higher than in control individuals. Meanwhile, serum Pb levels were positively associated with an increased risk of AD (OR = 1.10, 95% CI = 1.04-1.15). Lipidomic assay identified that four lipid metabolites, including phosphatidylcholine (PC) (33:2e), diacylglycerol (DG) (19:1e), sphingomyelins (SM) (d38:4), and phosphoserine (PS) (39:1), were significantly altered in the serum of AD patients. Among them, PC(33:2e) and SM(d38:4) were positively correlated with serum Pb levels. Moreover, PC(33:2e) and SM(d38:4) demonstrated mediation contributions of 60.49% and 20.38%, respectively, in the association between Pb exposure and AD incidence. Network toxicology suggests that Pb exposure may affect lipid metabolic processes in AD by modulating the activation of the MAPK, PI3K-Akt, AMPK, mTOR, and autophagy pathways. Our findings reveal novel insights into AD pathogenesis, suggesting that lipid metabolites may play a mediating role in the association between Pb exposure burden and AD risk.

Short-chain per- and polyfluoroalkyl substances (PFAS) are increasingly being used as substitutes for long-chain PFAS due to their lower bioaccumulation potential. However, their persistence and mobility can lead to toxicity and pose significant long-term health risks. Hence, the present study aims to investigate the toxicity and the molecular mechanisms associated with cancer and reproductive toxicity linked to short-chain PFAS based on network toxicology and molecular docking. The short-chain PFAS representatives used in this study include PFBA, PFBS, PFHxA, and PFHpA. The predicted biological targets for PFBA, PFBS, PFHxA, and PFHpA are 6, 2, 20, and 34, respectively. Potential targets from the disease library were identified and analyzed for protein-protein interactions and pathway enrichment. The top five targets were selected for molecular docking studies to examine interactions. Molecular docking indicated strong interactions between biological targets and pollutants, mainly through hydrogen bonds and salt bridges. Short-chain PFAS representatives have shown strong interaction with proteins such as HDAC3 (-6.133 kcal/mol), SHBG (-6.176 kcal/mol), PPARD (-6.355 kcal/mol and -6.205 kcal/mol), and FABP4 (-6.091 kcal/mol). This study also used molecular dynamics (MD) simulations to validate interactions, revealing significant dynamic behavior between proteins and ligands. Fourteen proteins linked to short-chain PFAS were associated with cancer and reproductive toxicity, with many targets common across diseases. Notably, PFHxA and PFHpA share several target proteins, suggesting similar effects in the body. Overall, the study provides an overview of the biological targets of short-chain PFAS and their potential health impacts.

This article presents a new, more efficient and accurate method for assessing fire and toxic smoke losses to structures, the risks associated with such, and the scope necessary to restore an affected property to its pre-fire loss condition. While the commonly utilized field practice of handling fires, using the S700 as a guide, has been to focus on visible damage and particulate accumulations, to test for the presence of soot, char, and ash (sometimes referred to as fire residue), and to attempt remediation and cleaning of the property. The method proposed herein is to test for microscopic particulates commonly produced by fire, including heavy metals, dioxins, and furans, to determine if toxic levels of identified particulates are present. When toxic levels are present, standard airflow and waterflow dynamics, as well as secondary contamination circulate the toxic particles throughout the property rendering the property effectively totaled as a result of the impracticality of alternative handling methods.

2,4-dichlorophenoxyacetic acid (2,4-D), a common herbicide, is widely used in agricultural activities. Prolonged and low-level exposure to 22,4-D increases the likelihood of adverse effects on human health. Nonetheless, the intricate toxicological mechanisms behind its influence on hypertension remain poorly understood. This study utilized ADMET, network toxicology, molecular docking, molecular dynamics, and gut microbiota analyses to explore the toxicological mechanisms underlying hypertension induced by 2,4-D. Common targets of 2,4-D and hypertension were retrieved from ChEMBL, SwissTargetPrediction, GeneCards, and OMIM databases. The ADMETlab (2.0) database was utilized to conduct ADMET analysis, which indicated potential health risks associated with 2,4-D. Eighteen potential targets associated with the toxicity of 2,4-D in relation to hypertension were identified and subsequently narrowed down to five key targets: ACE, REN, TNF, PPARG, and ADRB2 STRING database and Cytoscape software. Enrichment analyses through GO and KEGG revealed that 2,4-D primarily affects renin secretion and the renin-angiotensin system in its hypertensive toxicity. Molecular docking analysis results showed that 2,4-D has significant binding affinities with both ACE and REN. Molecular dynamics simulations indicated that the structural stability of the ACE-2,4-D complex was notably higher than that of the REN-2,4-D complex. Finally, 2,4-D may also interact with gut microbiota and their metabolites, potentially influencing TNF and PPARG pathways and contributing to the development of hypertension. This research offers a thorough assessment using computational techniques on the toxic effects of 2,4-D on hypertension, presenting approaches for systematically evaluating the health risks posed by 2,4-D.

Reactive oxygen species (ROS)-induced DNA oxidative damage is a significant manifestation of oxidative stress in the body and is closely associated with the onset and progression of various diseases. Although Pyripyropene A (PPPA) exhibits anti-tumor and anti-inflammatory activities, its antioxidant and protective effects against DNA oxidative injury remain unclear. In this study, using a hydrogen peroxide-induced oxidative injury model of L02 cells, it was found that PPPA could significantly reduce intracellular ROS and malondialdehyde (MDA) levels, enhance the activities of catalase (CAT) and reduced glutathione (GSH), and increase the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) clearance rate, confirming its antioxidant effect. Comet assay showed a reduction in DNA breakage, and down-regulation of phosphorylated histone (γ-H2AX) and 8-hydroxydeoxyguanosine (8-oxodG), indicating that it effectively alleviates DNA oxidative injury. Meanwhile, the upregulated expression of poly ADP-ribose polymerase (PARP) suggests that PPPA may promote repair by activating the DNA damage response (DDR). This study systematically clarify for the first time that PPPA exerts a protective effect by synergistically antioxidizing, reducing DNA injury, and potentially activating repair pathways, providing a theoretical basis for its application in neoplasm and oxidative stress-related diseases.

Caffeine, a widely consumed phytochemical, exhibits a dual and paradoxical role in modulating cellular responses to radiation, acting as both a radioprotector and radiosensitizer depending on context. This comprehensive review synthesizes evidence from , , and clinical studies to elucidate caffeine's multifaceted interactions with ionizing (gamma rays, X-rays) and non-ionizing (UV) radiation. Mechanistically, caffeine influences DNA repair pathways-notably inhibiting ATM/ATR checkpoint kinases-overrides G2/M cell cycle arrest, and modulates apoptosis through p53-dependent and independent pathways. While caffeine demonstrates radioprotective potential by mitigating oxidative stress, enhancing antioxidant defenses, and reducing chromosomal aberrations in normal tissues, it concurrently sensitizes cancer cells to radiation by disrupting DNA repair and amplifying mitotic catastrophe. Intriguingly, its effects vary by radiation type, dose, cell lineage (e.g. p53 status), and administration timing, underscoring its context-dependent utility. Preclinical studies highlight caffeine's capacity to attenuate radiation-induced hepatotoxicity, skin damage, and cataract formation, yet caution is warranted due to risks of exacerbating chromosomal instability and teratogenicity. Clinically, retrospective data suggest caffeine may reduce late radiotherapy toxicity in cervical cancer patients, though evidence remains sparse. This review underscores caffeine's potential as an adjuvant in radiotherapy but emphasizes the necessity for precision in its application, balancing therapeutic benefits against risks. Further research is critical to unravel dose-response dynamics, optimize timing, and validate clinical translatability across diverse radiation modalities.