Chemico-Biological Interactions最新文献

{"title":"Are PFAS alternatives safer? A network toxicology analysis suggests comparable or novel risks for hypertensive disorders of pregnancy","authors":"Ying Wang,&nbsp;Yingying Feng,&nbsp;Tingting Huang","doi":"10.1016/j.cbi.2026.111938","DOIUrl":"10.1016/j.cbi.2026.111938","url":null,"abstract":"<div><div>Per- and polyfluoroalkyl substances (PFAS), including legacy compounds (PFOA, PFOS) and their alternatives (HFPO-DA, OBS), pose potential risks for hypertensive disorders of pregnancy (HDP). This study systematically evaluated their mechanisms using network toxicology and molecular docking. Toxicity predictions indicated that alternatives exhibit significant multi-organ toxicity risks comparable to legacy PFAS. Network analysis revealed that alternatives not only share core HDP-related targets (STAT3, CASP3) with legacy PFAS but also engage unique targets (e.g., MTOR, AKT1), indicating broader pathogenic networks. Molecular docking demonstrated strong binding affinities, with OBS showing higher affinity for STAT3 and CASP3 than PFOS. Pathway enrichment analysis further implicated disruptions in placental development, immune inflammation, and vascular function. These findings suggest that PFAS alternatives do not present a superior safety profile and may introduce novel risks via distinct molecular pathways, underscoring the need for rigorous health risk assessments of these emerging contaminants.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"427 ","pages":"Article 111938"},"PeriodicalIF":5.4,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146095061","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":"Cytochrome P450-mediated detoxification and NF-κB/NLRP3 pathway-driven hepatotoxicity of emodin: Multiomics and laboratory evidence","authors":"Lili Wu ,&nbsp;Siyu Chen ,&nbsp;Qiyuan Yang ,&nbsp;Xing Li ,&nbsp;Lingyan Liu ,&nbsp;Shengjun Ji ,&nbsp;Shuaiyuan Tang ,&nbsp;Sihui Zhang ,&nbsp;Yan Wang ,&nbsp;Runzhi Chen ,&nbsp;Zhikun Zhan","doi":"10.1016/j.cbi.2026.111934","DOIUrl":"10.1016/j.cbi.2026.111934","url":null,"abstract":"<div><div>Emodin, a bioactive compound abundant in Chinese medicinal herbs, possesses broad therapeutic potential but raises safety concerns due to conflicting reports of hepatotoxicity. This study investigated the toxicological mechanisms underlying emodin-induced liver injury. Emodin (25–100 μM) elicited dose-dependent cytotoxicity in HepG2 cells, with the cytochrome P450 (CYP) enzymes CYP1A2 and CYP3A4 identified as the primary enzymes metabolizing emodin into hydroxylated products (M1-M3). The comparative cytotoxicity assay of emodin and its metabolites in HepG2 cells indicated that CYP-mediated metabolism functions as a critical detoxification pathway. Moreover, inhibition of CYP with 1-aminobenzotriazole (ABT, 500 μM) markedly enhanced emodin (12.5–100 μM) cytotoxicity in HepG2 cells. Similarly, ABT (50 mg/kg) markedly exacerbated emodin (400 mg/kg)-induced hepatotoxicity in mice following three weeks of co-administration. Transcriptomic profiling and validation experiments demonstrated that activation of the NF-κB/NLRP3 signaling axis contributes to emodin-induced hepatic injury. Metabolomic analyses further revealed perturbations in key pathways, including lipopolysaccharide (LPS) biosynthesis, sphingolipid metabolism, and cholesterol metabolism. Integrated multi-omics analysis identified a significant positive correlation between these metabolites (LPS, sphingosine, cholesterol) and NF-κB/NLRP3 pathway genes. These findings suggest that emodin-mediated upregulation of LPS, sphingosine, and cholesterol activates the NF-κB/NLRP3 pathway, subsequently triggering hepatic injury. Collectively, this study delineates the metabolic detoxification routes of emodin and provides mechanistic insight into its hepatotoxic potential.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"427 ","pages":"Article 111934"},"PeriodicalIF":5.4,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044422","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":"Molecular mechanisms of Aflatoxin B1-Induced renal injury and the detoxification potential of Taraxasterol: A review","authors":"Chenyuan Wang ,&nbsp;Xinyu Zhao ,&nbsp;Yansong Wang ,&nbsp;Hanshuo Li ,&nbsp;Yun Shi ,&nbsp;Yilong Cui","doi":"10.1016/j.cbi.2026.111936","DOIUrl":"10.1016/j.cbi.2026.111936","url":null,"abstract":"<div><div>Aflatoxins (AFs) are carcinogenic toxin metabolites produced by <em>Aspergillus fungi</em> in humid environments. They are widely distributed in nature and pose threats to human and animal health as well as crop production. Among the 21 identified AFs, aflatoxin B₁ (AFB₁) is classified as a natural Group I carcinogen by the World Health Organization. The kidneys are the primary target organs for AFB₁ toxicity, and the underlying mechanism involves oxidative stress, mitochondrial damage, dysfunction of mitophagy, inflammatory injury, and cell apoptosis. Taraxasterol (TAR) is a natural extract with antioxidant, anti-inflammatory, and immunomodulatory effects, which can alleviate the damage caused by AFB₁ by acting on these pathways. Therefore, this review focuses on the current toxic mechanism of AFB₁-induced kidney injury and deeply explores the potential mechanism of TAR in alleviating its toxicity, providing a reference for the application of AFB₁ detoxification.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"427 ","pages":"Article 111936"},"PeriodicalIF":5.4,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146042333","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":"m6A methylation dependent autophagy activation is required for anti-tumor effects of artesunate through ferroptosis in hepatocellular carcinoma","authors":"Yujia Li ,&nbsp;Min Shen ,&nbsp;Mengran Li ,&nbsp;Yangling Qiu ,&nbsp;Yingqian Wang ,&nbsp;Jiangjuan Shao ,&nbsp;Ji Xuan ,&nbsp;Shizhong Zheng ,&nbsp;Zili Zhang","doi":"10.1016/j.cbi.2026.111950","DOIUrl":"10.1016/j.cbi.2026.111950","url":null,"abstract":"<div><h3>Background &amp; aims</h3><div>Artesunate (Art), a semisynthetic derivative of Artemisinin isolated from the traditional Chinese medicinal plant <em>Artemisia annua L.</em>, has recently emerged as a candidate agent for hepatocellular carcinoma (HCC) therapy. Although accumulating preclinical evidence suggests its potent antitumor efficacy against HCC, the precise molecular mechanisms underlying its therapeutic effects remain poorly characterized. This investigation employs a multimodal approach to delineate the pharmacodynamic mechanism of Art in HCC pathogenesis, while establishing a mechanistic foundation for developing targeted combination therapies against this malignancy.</div></div><div><h3>Methods</h3><div>In vitro metastatic potential was quantified through standardized wound-healing assays and Matrigel-based transwell invasion systems. Autophagic flux dynamics and ferroptosis biomarkers were systematically profiled using commercial assay kits coupled with live-cell confocal imaging and Western blot. Mechanistic interrogation employed RIP-seq analysis and dual-luciferase reporter systems with in situ mutation controls. In vivo therapeutic efficacy was validated using orthotopic HCC xenograft models in immunocompromised BALB/c nude mice.</div></div><div><h3>Results</h3><div>Art demonstrated antitumor efficacy, significantly attenuating HCC cell motility and suppressing orthotopic xenograft growth. Mechanistic profiling revealed Art-induced ferroptosis through autophagy, mediated by m⁶A-dependent post-transcriptional regulation. Specifically, Art enhanced WTAP-mediated deposition of m⁶A modifications at the RRACH motif of ATG5 mRNA, facilitating YTHDC2-dependent translation. This epitranscriptomic reprogramming increased ATG5 protein synthesis, triggering autophagy dependent ferritin degradation and subsequent ferroptosis.</div></div><div><h3>Conclusion</h3><div>Art emerges as a clinically potential HCC therapeutic that elicits its oncosuppressive activity through WTAP/YTHDC2-mediated m⁶A methylation of ATG5 transcripts, thereby causes ferroptosis of HCC mediated by autophagy.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"427 ","pages":"Article 111950"},"PeriodicalIF":5.4,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146101253","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-vitro and in-vivo CYP3A4 Variants: Neratinib metabolism and drug interaction risk","authors":"Zheyan Zhang ,&nbsp;Xiaoyu Huang ,&nbsp;Chen Gan ,&nbsp;Shuman Xue ,&nbsp;Yan He ,&nbsp;Congcong Wen","doi":"10.1016/j.cbi.2026.111935","DOIUrl":"10.1016/j.cbi.2026.111935","url":null,"abstract":"<div><div>To investigate the effects of metabolic enzyme activity inhibition and genetic polymorphisms on the pharmacokinetics and pharmacodynamics of neratinib, we employed a combined approach of molecular docking and an <em>in-vitro</em> enzymatic reaction system to identify potential inhibitors in this study. The levels of neratinib and its metabolite were quantified using ultra performance liquid chromatography with tandem mass spectrometry. Additionally, <em>in-vivo</em> studies were conducted using Female Sprague-Dawley rats, and subsequent metabolic enzyme kinetics analyses were performed to evaluate the impact of genetic polymorphisms on neratinib metabolism. Among the 10 drugs screened, the antihistamine loratadine showed a pronounced inhibitory effect on neratinib metabolism in vitro, with a relative inhibition rate of 94.3 %, significantly increasing the systemic exposure of neratinib in rats. This finding is attributed to the mixed-type inhibition of liver microsome activity by loratadine. Furthermore, the differential inhibitory effects of loratadine toward CYP3A4.1 and CYP3A4.34 underscore the role of <em>CYP3A4</em> genetic polymorphisms in modulating the inhibitory potency of loratadine toward neratinib. In conclusion, our study suggests that coadministration of loratadine and genetic polymorphisms in <em>CYP3A4</em> can significantly influence neratinib metabolism, necessitating caution regarding potential drug-drug interactions in clinical settings.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"427 ","pages":"Article 111935"},"PeriodicalIF":5.4,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146026111","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":"Prenatal hydroxychloroquine exposure-induced morphological and functional changes in multiple organs of fetal mice and its characteristics","authors":"Yifan Liu ,&nbsp;Lingbo Rong ,&nbsp;Ailikaiti Aihemaitijiang ,&nbsp;Xiaoqi Zhao ,&nbsp;Wen Zhang ,&nbsp;Hui Wang","doi":"10.1016/j.cbi.2026.111927","DOIUrl":"10.1016/j.cbi.2026.111927","url":null,"abstract":"<div><div>Hydroxychloroquine is clinically widely used in the treatment of various autoimmune diseases and is one of the drugs that can be used throughout pregnancy. However, studies have suggested that prenatal hydroxychloroquine exposure (PHE) may affect early development of offspring, but a systematic and comprehensive evaluation is still lacking. Based on clinical medication regimens, this study administered hydroxychloroquine at different doses (20, 40, 80 mg/kg·d) to pregnant mice via oral gavage throughout gestation, aiming to observe changes in pregnancy outcomes, blood phenotypes of mothers and fetuses, and morphological and functional development of multiple fetal organs, as well as to explore the potential mechanisms.Results showed that PHE increased resorbed fetuses, stillbirths, and IUGR, and altered multiple blood indicators with the changes being particularly significant in feteses. The multi-organ functions were changed, inhibiting long bone and kidney development, adrenal steroid synthesis, placental trophoblast syncytialization, and promoting alveolar surfactant and hepatic bile acid synthesis, with females more affected gender differences and dose-effect relationship. Morphology confirmed abnormalities in long bones, gonads, and lungs. Correlation analysis showed multi-organ functional changes in females positively correlated with autophagy and apoptosis. This study confirms PHE causes adverse outcomes and abnormal multi-organ development, possibly via inhibited autophagy and increased apoptosis. This study has deepened our understanding of the developmental toxicity of hydroxychloroquine and provided experimental evidence for long-term hazard assessment and early prevention.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"427 ","pages":"Article 111927"},"PeriodicalIF":5.4,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146042351","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 vitro recapitulation of drug metabolite partitioning into the bile and blood using the icHep system consisting of hepatocytes with an induced open-form bile canaliculus","authors":"Yuya Nakazono ,&nbsp;Naoki Ishiguro ,&nbsp;Mutsumi Inamatsu ,&nbsp;Atsuo Kobayashi ,&nbsp;Yoshiki Mochizuki ,&nbsp;Takashi Watanabe ,&nbsp;Yukihide Momozawa ,&nbsp;Chise Tateno ,&nbsp;Ikumi Tamai ,&nbsp;Hiroshi Arakawa","doi":"10.1016/j.cbi.2026.111931","DOIUrl":"10.1016/j.cbi.2026.111931","url":null,"abstract":"<div><div>For <em>in vitro</em> studies that predict the safety of systemically circulating drug metabolites, evaluating the formation and biliary excretion of hepatic drug metabolites in human hepatocytes is necessary. However, conventional sandwich-cultured hepatocytes (SCH) form closed bile canaliculi that preclude direct collection of excreted biliary metabolites. Therefore, this study assessed whether primary cultured hepatocytes with an induced open-form bile canaliculus (icHep) provide a suitable system for evaluating the partitioning of drug metabolites produced in hepatocytes into the bile-side and blood-side chambers. Hepatocytes derived from human liver chimeric mice were cultured on claudin-1-coated plates, which facilitated the formation of an open bile canalicular lumen, as confirmed by co-immunostaining for multidrug resistance-associated protein 2 and zonula occludens 1. RNA-sequencing analysis revealed that the expression of representative pharmacokinetic-related genes in the icHep system were comparable with those in conventional SCH. Following the addition of the parent drugs to the blood-side chamber of the permeation assay, metabolites were successfully collected from both the blood- and bile-side chambers. Ziprasidone sulfoxide and mycophenolic acid glucuronide were predominantly recovered from blood-side chamber, whereas celecoxib carboxylic acid and SN-38 glucuronide were preferentially excreted into the bile-side chamber. The partitioning of metabolites observed in the icHep system was consistent with human <em>in vivo</em> data. Overall, the icHep system enables evaluation of drug metabolite partitioning into the bile- and blood-side. Hence, this system represents a physiologically relevant <em>in vitro</em> system for human pharmacokinetic studies.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"427 ","pages":"Article 111931"},"PeriodicalIF":5.4,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146032003","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":"Recurrent amoxicillin exposure disrupts colonic homeostasis through oxidative stress, DNA repair dysregulation, and gut dysbiosis-driven inflammation","authors":"Nabila Akhtara,&nbsp;Manuj Kr Bharali","doi":"10.1016/j.cbi.2026.111939","DOIUrl":"10.1016/j.cbi.2026.111939","url":null,"abstract":"<div><div>The present study investigated the impact of recurrent amoxicillin exposure on colonic health in a mouse model, applying a multi-parametric approach. Twenty animals were randomly divided into two groups, out of which one group received oral amoxicillin (100 mg/kg BW), administered every other week for twelve weeks. Histological and ultra-structural analyses (SEM and TEM) of colonic tissues revealed crypt degeneration, mucosal thinning, and inflammatory cell infiltration in the treated group. Biochemical assays demonstrated significantly elevated lipid peroxidation along with reduced antioxidant defences, indicative of oxidative stress. Immunohistochemistry confirmed oxidative DNA damage, accompanied by aberrant expression of DNA repair genes, indicating impaired genomic maintenance. Faecal microbiota profiling showed a pronounced loss of microbial load and enrichment of opportunistic pathogens, alongside a paradoxical increase in short-chain fatty acid levels. These alterations correlated with significantly upregulated inflammatory gene expression (TNF-α, IFN-γ, IL-6, IL-17 &amp; IL-1β), indicating microbiome destabilization and heightened inflammatory signalling. Overall, recurrent amoxicillin exposure disrupted colonic homeostasis through dysbiosis, oxidative stress, genotoxicity, and inflammation, underscoring the potential risks of antibiotic therapy.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"427 ","pages":"Article 111939"},"PeriodicalIF":5.4,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075943","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":"Multi-omics and in silico evidence reveal perospirone-induced developmental neurotoxicity in zebrafish via AKT/FOXO3a-mediated apoptosis","authors":"Zhe Feng ,&nbsp;Lisheng Zhu ,&nbsp;Wentian Li ,&nbsp;Fang Wang ,&nbsp;Qianqian Cheng ,&nbsp;Huihui Yang ,&nbsp;Yuqing Huang ,&nbsp;Wenqi Gao ,&nbsp;Hui Lu ,&nbsp;Junbao Wang ,&nbsp;Han Xiao ,&nbsp;Hongjian Gong","doi":"10.1016/j.cbi.2026.111904","DOIUrl":"10.1016/j.cbi.2026.111904","url":null,"abstract":"<div><div>Perospirone, an atypical antipsychotic increasingly detected in aquatic environments, raises concerns regarding potential developmental hazards in early vertebrates. As an emerging personal care product (PPCP) contaminant, its developmental neurotoxicity remains poorly characterized. To evaluate its biological effects, zebrafish embryos were exposed to perospirone (nominal 0.1, 1, 10 mg/L) from 5 to 120 hpf. At 5 dpf, larvae exposed to 1 mg/L displayed increased locomotion with anxiety-like features, whereas exposure to 10 mg/L was associated with reduced body length and hyperactivity suppression, together with elevated Caspase 9 and Pro- Caspase 3 expression consistent with apoptosis activation. Neurotransmitter profiling revealed an increase in 5-HIAA and decreases in dopamine and glutamine, accompanied by transcriptomic enrichment of pathways related to serotonergic signaling, oxidative stress, and FOXO/AKT regulation. Besides, molecular docking revealed high-affinity perospirone-AKT1 binding (−7.88 kcal/mol). These multi-omics findings establish that perospirone-induced developmental neurotoxicity stems from AKT/FOXO3a-mediated apoptosis, providing critical insights into its neurotoxicological profile and environmental risks as an emerging pharmaceutical contaminant.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"426 ","pages":"Article 111904"},"PeriodicalIF":5.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145936753","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":"Trojan horse tactics: Naphthalimide polyamine conjugates revolutionize cancer treatment","authors":"Zhiyong Tian ,&nbsp;Luyao Tian ,&nbsp;Chaojie Wang ,&nbsp;Suiqing Chen","doi":"10.1016/j.cbi.2026.111926","DOIUrl":"10.1016/j.cbi.2026.111926","url":null,"abstract":"<div><div>Naphthalimide polyamine conjugates (NPCs) represent a disruptive advance in anticancer drug development by employing multi-target strategies to overcome the limitations of traditional DNA intercalators. Unlike conventional naphthalimide drugs such as Amonafide, which show limited tumor inhibition (46.91 %) and significant toxicity, NPCs leverage the polyamine transporter (PAT) system for selective tumor accumulation—a ‘Trojan horse’ effect. This review highlights three key advances: (1) optimizing polyamine chain length and aromatic ring substitution (e.g., 3-nitro) to improve PAT affinity and DNA intercalation; (2) adopting multimodal mechanisms, including interference with polyamine metabolism via the SSAT/PAO pathway, leading to autophagy, EMT prevention, and DNA damage; and (3) developing PAT-mediated targeting and nanocarrier systems to enhance solid tumor penetration. Critically, the compelling <em>in vivo</em> efficacy of several lead NPCs, such as conjugate 5b, which achieved &gt;75 % inhibition of tumor growth and metastasis in HCC models, provides a solid foundation for this drug class. Innovations like dual-target conjugates (e.g., flavone-naphthalimide-polyamine) and computational modeling of drug-likeness and binding modes are emerging as promising tools for personalized oncology. Despite facing challenges in synthetic complexity and clinical translation, NPCs hold potential to address key clinical hurdles—poor pharmacokinetics, tumor penetration, and drug resistance—offering a breakthrough strategy for invasive and metastatic cancers.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"426 ","pages":"Article 111926"},"PeriodicalIF":5.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145999500","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}