Chemico-Biological Interactions最新文献

{"title":"The role of selenium in modulating sperm count and ferroptosis pathways in male reproductive health","authors":"Wenrui Lu ,&nbsp;Yuxia Yang ,&nbsp;Tianqin Deng ,&nbsp;Fan Xiao ,&nbsp;Yunqi Luo ,&nbsp;Peiyi Liu ,&nbsp;Jianjun Liu","doi":"10.1016/j.cbi.2025.111889","DOIUrl":"10.1016/j.cbi.2025.111889","url":null,"abstract":"<div><div>This study elucidates the role of selenium in male fertility via the SLC7A11-GPX4 ferroptosis pathway. In a six-week dietary intervention, KM mice fed a selenium-deficient diet (&lt;0.01 mg/kg) exhibited significantly decreased prostate indices (<em>P</em> &lt; 0.05) and disrupted seminiferous tubule structure compared to controls, while epididymal sperm counts showed a decreasing trend that did not reach statistical significance. Selenium supplementation (sodium selenite, 3.2 mg/kg) significantly increased testis indices (<em>P</em> &lt; 0.05) and improved tubule organization, with a non-significant increase in sperm counts. Crucially, testicular <em>gpx4</em> (<em>P</em> &lt; 0.001) and <em>slc7a11</em> (<em>P</em> &lt; 0.05) gene expression were significantly downregulated in the deficient group. In GC2-spd spermatocytes, the ferroptosis inducer Erastin significantly suppressed proliferation (<em>P</em> &lt; 0.05) and induced ferroptotic ultrastructural damage. Selenomethionine (SeM,5.0 μM) significantly attenuated Erastin-induced proliferation suppression and upregulated GPX4 protein (<em>P</em> &lt; 0.05), while sodium selenite showed non-significant protection. Lentiviral GPX4 knockdown confirmed SeM's effects are GPX4-dependent. In human studies, seminal selenium levels were comparable between groups and showed no correlation with GPX4 or SLC7A11. Oligozoospermia cases exhibited significantly decreased seminal GPX4 (<em>P</em> &lt; 0.001) but unchanged SLC7A11 levels (<em>P</em> = 0.900). However, multivariable analysis identified lower GPX4 and higher SLC7A11 (per SD increase) as independent risk factors (GPX4: OR&lt;0.001, <em>P</em> &lt; 0.001; SLC7A11: OR = 1.48, <em>P</em> = 0.032), revealing a characteristic biomarker dissociation However, multivariable analysis identified lower GPX4 and higher SLC7A11 (per SD increase) as independent risk factors (GPX4: OR&lt;0.001, <em>P</em> &lt; 0.001; SLC7A11: OR = 1.48, <em>P</em> = 0.032), revealing a characteristic biomarker dissociation. In conclusion, selenium significantly influences testicular morphology and ferroptosis pathway gene expression in vivo, although its effects on sperm count under these experimental conditions were not statistically significant. In vitro, Selenomethionine effectively mitigates Erastin-induced ferroptosis and proliferation suppression in spermatocytes primarily through GPX4-mediated mechanisms. In patients with oligozoospermia, seminal plasma GPX4 concentration was significantly decreased and was identified as an independent protective factor, while SLC7A11 level was associated with increased risk in multivariable analysis; neither biomarker correlated with seminal plasma selenium concentration.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"426 ","pages":"Article 111889"},"PeriodicalIF":5.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145954320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In silico and in vitro investigation of the safety and immunomodulatory mechanisms of 7-hydroxyflavone","authors":"Vanessa da Silva Oliveira ,&nbsp;Dahara Keyse Carvalho Silva ,&nbsp;Maria Vitória Gomes das Neves ,&nbsp;Sergio Santos Silva Junior ,&nbsp;Jônatas Sousa Pires dos Santos ,&nbsp;Claudia Valeria Campos de Souza ,&nbsp;José Maria Barbosa Filho ,&nbsp;Osvaldo Andrade Santos-Filho ,&nbsp;Milena Botelho Pereira Soares ,&nbsp;Cássio Santana Meira","doi":"10.1016/j.cbi.2026.111908","DOIUrl":"10.1016/j.cbi.2026.111908","url":null,"abstract":"<div><div>7-Hydroxyflavone (7HF) is a natural flavonoid with recognized antioxidant and anti-inflammatory properties, but its immunomodulatory potential and underlying molecular mechanisms remain poorly defined. This study investigated the immunomodulatory activity of 7HF in human peripheral blood mononuclear cells (PBMCs) and murine splenocytes through <em>in silico</em> and <em>in vitro</em> approaches. Pharmacokinetic and toxicity predictions were obtained with ProTox 3.0. Cytotoxicity and hemolysis assays evaluated the compound safety, whereas lymphoproliferation and cytokine secretion (IL-2 and IFN-γ) were analyzed in PHA- or ConA-stimulated cells with or without the glucocorticoid-receptor (GR) antagonist RU-486. The expression of inflammatory mediators and signaling molecules was quantified by RT-qPCR, and molecular docking assessed the affinity of 7HF for calcineurin and GR. 7HF showed favorable pharmacokinetic predictions, low acute toxicity, and moderate CC₅₀ values in murine splenocytes (74.2 ± 6.1 μM) and human PBMCs (60.1 ± 1.9 μM), with no cytotoxic or hemolytic effects at immunomodulatory concentrations. The compound significantly inhibited lymphocyte proliferation and cytokine production in activated PBMCs and splenocytes, effects partially reversed by RU-486, indicating GR involvement. Gene-expression analysis revealed downregulation of calcineurin subunits (PPP3CA/B/C), PLCG1, NFAT1/2, and pro-inflammatory mediators, with additional modulation of PI3K/AKT, GR, NF-κB/AP-1, and JAK/STAT pathways. Molecular docking confirmed stable interactions of 7HF with both calcineurin and GR, with ChemPLP scores comparable to dexamethasone. Overall, 7HF exhibited selective immunosuppressive activity by modulating multiple signaling pathways involved in lymphocyte activation, supporting its potential as a safe lead compound for developing novel therapeutic agents.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"426 ","pages":"Article 111908"},"PeriodicalIF":5.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cyflumetofen disrupts the blood-brain barrier and induces neurotoxicity in zebrafish larvae","authors":"Wei-Guo Wang ,&nbsp;Yi-Min Duan ,&nbsp;Wen-Ping Xu,&nbsp;Li-Ming Tao,&nbsp;Yang Zhang,&nbsp;Jia-Gao Cheng","doi":"10.1016/j.cbi.2026.111911","DOIUrl":"10.1016/j.cbi.2026.111911","url":null,"abstract":"<div><div>Cyflumetofen is a novel non-systemic acylacetonitrile miticide widely used in agriculture to control various harmful mites. However, its potential safety risks to the nervous system of non-target organisms require further evaluation. Cyflumetofen induces developmental toxicity in zebrafish larvae, manifested as pericardial edema, yolk sac enlargement, and reduced body length. To evaluate the impact on the nervous system, cyflumetofen was found to damage neuronal and motor neuron cells in zebrafish larvae, reduce locomotor activity, and alter brain tissue structure. Additionally, cyflumetofen induces apoptosis in zebrafish larvae and leads to oxidative stress, which may be a critical pathway contributing to neurotoxicity. Furthermore, cyflumetofen disrupts the blood-brain barrier (BBB) structure in zebrafish larvae and reduces the levels of tight junction (TJ) proteins. Molecular-level studies reveal that cyflumetofen interferes with the Wnt/β-catenin signaling pathway and upregulates the expression levels of genes associated with Parkinson's disease (PD) pathogenesis (<em>pink1</em>, <em>parkin</em>, and <em>lrrk2</em>).</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"426 ","pages":"Article 111911"},"PeriodicalIF":5.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145974893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comments on “Trimethylamine N-oxide induced cognitive impairment through disruption of blood-brain barrier by inhibiting TGF-β pathway”","authors":"Jiehua Han","doi":"10.1016/j.cbi.2026.111910","DOIUrl":"10.1016/j.cbi.2026.111910","url":null,"abstract":"","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"426 ","pages":"Article 111910"},"PeriodicalIF":5.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145954329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Streptomycin mitigates methylglyoxal-induced carbonyl stress through its antiglycation activity: A drug-repurposing approach for carbonyl stress-related disorder","authors":"Shin Koike ,&nbsp;Haruka Mitsuhashi ,&nbsp;Aoi Takahashi ,&nbsp;Mari Ishizaki ,&nbsp;Atsushi Kishida ,&nbsp;Yuki Ogasawara","doi":"10.1016/j.cbi.2026.111901","DOIUrl":"10.1016/j.cbi.2026.111901","url":null,"abstract":"<div><div>Advanced glycation end-products (AGEs), having multiple structures, are formed at the sites where the carbonyl groups of the reducing sugars bind to the free amino groups of the proteins through the Maillard reaction.</div><div>The accumulation of AGEs, which are generated when carbonyl compounds produced in the process of glucose metabolism react with proteins, is involved in various carbonyl stress-related diseases. Meanwhile, guanidine compounds, represented by aminoguanidine, have possibilities as a scavenger that inhibits AGE formation by directly reacting with carbonyl compounds. We here focused on existing drugs with a guanidine-like structure and estimated the reactivity of nine drugs, including aminoguanidine, with methylglyoxal (MGO), a glucose metabolite, to assess their potential application to carbonyl stress-induced diseases. Considering the results of the two screening methods, we concentrated on streptomycin, which exhibited stable scavenging activity, and evaluated its inhibitory effect on the MGO-induced AGE formation in proteins in vitro. Furthermore, the effects of streptomycin on carbonyl protein accumulation in the cells and the MGO-induced cytotoxicity were investigated to elucidate the cytoprotective potential against glycation. The results revealed that streptomycin added to the culture medium with MGO suppressed the MGO-induced carbonylation of intracellular proteins and exerted a protective effect by alleviating the toxicity of MGO in a study using human-derived neuroblastoma SH-SY5Y. These findings suggest that the clinically available streptomycin has a potential to be utilized for carbonyl stress-related diseases as a repurposing drug.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"425 ","pages":"Article 111901"},"PeriodicalIF":5.4,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cadmium exposure impaired the uterine decidualization through inducing the imbalance of mitochondrial fusion and fission","authors":"Yin-Fei Xing ,&nbsp;Liang Yue ,&nbsp;Chen-Hao Wang ,&nbsp;Cai-Jiao Zhou ,&nbsp;Jia-Qi Ye ,&nbsp;Shi-Jie Li ,&nbsp;Bin Guo","doi":"10.1016/j.cbi.2026.111906","DOIUrl":"10.1016/j.cbi.2026.111906","url":null,"abstract":"<div><div>Cadmium (Cd), a widespread environmental pollutant, has toxic effects on spermatogenesis and sperm motility, but its role in uterine decidualization remains unknown. This study revealed that Cd exposure during early pregnancy might impair the uterine decidualization along with the disordered proliferation and apoptosis of stromal cells, resulting in the reduction of mouse neonatal number and birth weight. After disrupting the binding of Ca²⁺ and LNR-C, Cd exposure ligand-independently activated the NOTCH1 signaling and then restrained the expression of nuclear TAZ via RBPJ-targeting LATS. Further analysis suggested that Cd exposure contributed to the depletion of glutathione via Gclc that was identified as a direct downstream target of TAZ/TEAD, resulting in intracellular ROS accumulation and subsequent mitochondrial dysfunction. Meanwhile, Cd exposure prevented mitochondrial fusion and facilitated mitochondrial fission together with the fragmented mitochondria, whereas attenuation of intracellular ROS alleviated the imbalance between mitochondrial fusion and fission by Cd exposure. Moreover, improvement of mitochondrial fusion insufficiency and excessive fission rescued the impairment of Cd on decidualization. Collectively, Cd exposure impaired the uterine decidualization through inducing the imbalance of mitochondrial fusion and fission. These findings reveal the toxic effect of Cd on female reproduction and serve as a risk factor for adverse pregnancy outcomes.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"425 ","pages":"Article 111906"},"PeriodicalIF":5.4,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein adduct formation between RuBisCO and V-type organophosphorus nerve agents","authors":"Qian Wang,&nbsp;Jin Wang,&nbsp;Hongmei Wang,&nbsp;Meng Jin,&nbsp;Runli Gao,&nbsp;Xiaogang Lu","doi":"10.1016/j.cbi.2025.111864","DOIUrl":"10.1016/j.cbi.2025.111864","url":null,"abstract":"<div><div>Organophosphorus nerve agents (OPNAs) are highly toxic compounds that disrupt the central nervous system through irreversible inhibition of acetylcholinesterase. Classified as chemical weapons under the Chemical Weapons Convention (CWC), OPNAs necessitate reliable and extended-window detection methods for exposure verification. To expand the range of biomarker candidates for OPNA exposure in food matrices, this study investigated the <em>in vitro</em> formation of adducts between ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO)—a predominant protein in spinach—and V-type OPNAs. Mass spectrometry identified 13 reproducibly adducted peptides; notably, 5 peptides showed conserved covalent modification sites across all three OPNAs investigated in this study (VX, VR, and Vs), indicating agent-independent targeting. The modified sequences GHYLNATAGTCEDMMK (Y239/C247), WSPELAAACEVWK (C459), YGRPLLGCTIKPK (Y165), and FLFC∗AEALYK (C221) exhibited high adduct stability. These stable and modified peptides are promising biomarkers for OPNA-exposure tracking. Thus, this study provides a basis for the forensic analysis of organophosphorus toxicant residues and food safety incident investigations.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"425 ","pages":"Article 111864"},"PeriodicalIF":5.4,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145783769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N-homocysteinylation of ferritin and associated changes in iron metabolism as potential drivers of vascular endothelial dysfunction in hyperhomocysteinemia","authors":"Andzelika Borkowska ,&nbsp;Ulana Juhas ,&nbsp;Szczepan Olszewski ,&nbsp;Joanna Reczkowicz ,&nbsp;Pawel Wityk ,&nbsp;Banu Akdogan ,&nbsp;Hans Zischka ,&nbsp;Jedrzej Antosiewicz","doi":"10.1016/j.cbi.2025.111890","DOIUrl":"10.1016/j.cbi.2025.111890","url":null,"abstract":"<div><div>Hyperhomocysteinemia contributes to various diseases, including cardiovascular and neurodegenerative disorders. While previous research indicates iron's role in hyperhomocysteinemia, the underlying molecular interactions remain poorly understood. Our previous study demonstrated that homocysteine significantly increases ferritin levels, linked to disruptions in the Akt-FOXO3a pathway, though the reasons for these increases are unclear. In the present study, we investigated these mechanisms, evidencing that homocysteine thiolactone (HcyT) similarly increases the levels of Ferritin L and H in HUVEC, but not in SH-SY5Y cells. This ferritin upregulation was accompanied by elevations labile iron pools. Furthermore, in cells exposed to HcyT, there was an increase in proteins responsible for exporting iron, such as ferroportin and APP. Additionally, intracellular iron chaperones, such as PCBP1 and PCBP2, were significantly dysregulated, while the level of the transferrin receptor—the protein responsible for importing iron into the cell—was decreased. These results suggest a compensatory protective response to iron accumulation in HcyT-treated cells. Pre-incubating with H₂O₂ increased cellular sensitivity to HcyT-induced toxic effects, providing indirect evidence for the involvement of an iron-dependent cell death mechanism in endothelial cells HUVEC. We discovered that HcyT triggers the process of N-homocysteinylation of ferritin H, which most likely impairs its function. This explains the steady increase in ferritin and LIP levels in the studied cell model. In conclusion, we are the first to demonstrate that HcyT disrupt iron metabolism at multiple levels, including storage, export, import, and intracellular transport. Our findings indicate that these disturbances are caused by N-homocysteinylation of ferritin.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"425 ","pages":"Article 111890"},"PeriodicalIF":5.4,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145879584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ALKBH5 enhances cadmium-induced stemness enrichment and proliferation of colon cancer cells via m6A-dependent regulation of AXIN2 and activation of Wnt/β-catenin signaling","authors":"Jianing Hu ,&nbsp;Shuhui Zhu ,&nbsp;Xinze He ,&nbsp;Bangqi Cen ,&nbsp;Zhuangzhuang Xu ,&nbsp;Fei Han ,&nbsp;Kun Ding ,&nbsp;Min Jiang ,&nbsp;Yansu Chen ,&nbsp;Yefei Huang","doi":"10.1016/j.cbi.2026.111905","DOIUrl":"10.1016/j.cbi.2026.111905","url":null,"abstract":"<div><div>Cadmium (Cd) is a carcinogenic heavy metal with a long biological half-life that has been implicated in the development of colorectal cancer (CRC). However, the mechanisms underlying Cd-induced CRC malignancy remain incompletely understood. Cancer stem cells (CSCs), which are characterized by self-renewal, pluripotency and unlimited proliferative potential, are believed to be responsible for the initiation, progression and recurrence of CRC. The aim of this study was to investigate the long-term effects of Cd on stemness enrichment and proliferation in colon cancer cells, and to identify the key signaling pathways involved. Our results demonstrated that chronic Cd exposure enhanced sphere formation and increased the expression of stem cell-like markers (CD44, OCT4, SOX2, and NANOG) in colon cancer cells. Colony formation assays, CCK-8 assays, and xenograft models in nude mice further confirmed that Cd significantly promoted cell proliferation. Mechanistically, Cd reduced N6-methyladenosine (m6A) methylation in mRNA by upregulating the m6A demethylase ALKBH5. Knockdown of ALKBH5 attenuated Cd-induced stemness enrichment and proliferation. ALKBH5 was found to demethylate the m6A of AXIN2 mRNA, reducing IGF2BP1-mediated stabilization of AXIN2 mRNA, leading to its destabilization and reduced expression, which subsequently hyperactivated the Wnt/β-catenin signaling. These results highlight the role of the ALKBH5–m6A–AXIN2–Wnt/β-catenin axis in Cd-induced stemness and proliferation in colon cancer, offering new insights into Cd-associated CRC development.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"425 ","pages":"Article 111905"},"PeriodicalIF":5.4,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145919393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The expanding frontiers of gallic acid: From dual chemistry and pharmacology to innovative technological applications","authors":"Woo Hyun Park","doi":"10.1016/j.cbi.2026.111899","DOIUrl":"10.1016/j.cbi.2026.111899","url":null,"abstract":"<div><div>Gallic acid (3,4,5-trihydroxybenzoic acid), a phenolic compound of botanical origin, exhibits a historically significant role within the annals of traditional pharmacopeia and is currently garnering substantial academic attention for its multifaceted utility in contemporary scientific and technological spheres. In this treatise, a comprehensive synthesis of multidisciplinary insights is presented, wherein the dual redox behavior of gallic acid—characterized by its function as an antioxidant through radical scavenging and metal coordination, or alternatively as a pro-oxidant via Fenton-type reactions and the depletion of intracellular glutathione (GSH)—is established as the primary conceptual framework for its functional versatility. The pharmacological dimensions investigated herein comprise anti-inflammatory activities mediated by the inhibition of NF-κB and mitogen-activated protein kinase (MAPK) pathways; selective antineoplastic cytotoxicity facilitated by the generation of reactive oxygen species (ROS) and subsequent induction of apoptosis; metabolic regulation attained through the activation of AMPK and PPAR-γ; and neuroprotection enabled via the modulation of GSK3β–Nrf2 signaling. Notwithstanding its extensive therapeutic potential, the clinical translation of gallic acid is currently impeded by its classification as a Biopharmaceutics Classification System (BCS) Class III compound, reflecting a sub-optimal pharmacokinetic profile. Strategic interventions, including molecular derivatization and nanotechnology-based delivery architectures, are evaluated as means to circumvent these physiological barriers. Furthermore, this review delineates innovative applications in active packaging, environmental remediation, and the nascent frontier of metal–phenolic networks (MPNs). Through the integration of these disparate research trajectories, an AI-driven and sustainable roadmap is proposed to fully harness the redox duality of gallic acid in both biomedical and industrial implementations.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"425 ","pages":"Article 111899"},"PeriodicalIF":5.4,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}