Chemico-Biological Interactions最新文献

{"title":"Potent inhibition of human monoamine oxidase A and B by phenolic compounds and polyunsaturated fatty acids in tobacco smoke","authors":"Sa Weon Hong ,&nbsp;Ali Heydari ,&nbsp;Paris R. Watson ,&nbsp;Paul H. Teesdale-Spittle ,&nbsp;Rachel Page ,&nbsp;Peter T. Northcote ,&nbsp;Robert A. Keyzers ,&nbsp;Mikhail Vyssotski ,&nbsp;Penelope Truman","doi":"10.1016/j.cbi.2025.111477","DOIUrl":"10.1016/j.cbi.2025.111477","url":null,"abstract":"<div><div>Smoking is a main cause of premature death and preventable disease in the world. Interestingly, animal studies indicate that inhibition of monoamine oxidase (MAO), key enzymes for the degradation of neurotransmitters, increased self-administration of nicotine. The purpose of this study was to identify and characterize the potential MAO inhibitors in tobacco smoke responsible for MAO inhibition in smokers. A bioassay-guided isolation from an extract of tobacco smoke showed that catechol, 4-methylcatechol, hydroquinone, α-linolenic acid, and linoleic acid all displayed potent human MAO inhibitory activity. Additionally, the tobacco catechols 4-ethylcatechol and 4-vinylcatechol were included to test their inhibitory potencies. Catechol, 4-methylcatechol, 4-ethylcatechol, and hydroquinone are potent and irreversible MAO inhibitors. Among the phenolic compounds tested, 4-methylcatechol and 4-ethylcatechol inhibited MAO A with IC₅₀ values of 10.0 and 12.6 μM, respectively, reducing to 0.27 and 0.43 μM after 1 h preincubation. In addition, α-linolenic acid and linoleic acid competitively inhibited MAO A with <em>K</em>_i values of 10.50 and 6.95 μM, respectively. These results suggest that MAO inhibition by phenolics and polyunsaturated fatty acids in tobacco smoke may be important contributors to the MAO inhibition experienced by smokers and to the enhancement of nicotine dependence this MAO inhibition is believed to cause.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"413 ","pages":"Article 111477"},"PeriodicalIF":4.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The influence and mechanisms of exogenous aryl hydrocarbon receptor ligands on the viability of mouse germ cells","authors":"Yimin Cheng ,&nbsp;Yebin Yang ,&nbsp;Chen Chen ,&nbsp;Feifeng Zhang ,&nbsp;Shenglin Peng ,&nbsp;Xinsheng Xiao ,&nbsp;Zhen Peng","doi":"10.1016/j.cbi.2025.111478","DOIUrl":"10.1016/j.cbi.2025.111478","url":null,"abstract":"<div><div>Environmental pollution is a significant contributor to male infertility. Numerous environmental pollutants, such as PCB118, act as exogenous ligands for the aryl hydrocarbon receptor (AhR). However, the role of AhR in mediating the effects of environmental pollutants on male reproductive functions remains inadequately understood. In the present study, we assessed the viability of GC-1 and GC-2 cells using the CCK-8 assay. Immunofluorescence and Western blotting techniques were employed to investigate the distribution and protein expression levels of AhR within these cell lines. Alterations in reactive oxygen species (ROS) levels and mitochondrial membrane potential (MMP) were evaluated using DCFH-DA dye and the JC-1 assay, respectively. Furthermore, we investigated changes in the expression levels of Nrf2, Cleaved-Caspase 3, Cleaved-Caspase 8, Bcl-2, and Bax through Western blot analysis. Our findings indicate that PCB118 and the AhR-specific agonist CAY10465 diminish the viability of GC-1 and GC-2 cells, facilitate the nuclear translocation and expression of AhR protein, elevate ROS levels, and reduce MMP. Moreover, these agents markedly increase the levels of Cleaved-Caspase 3 and Cleaved-Caspase 8 while decreasing the Bax/Bcl-2 ratio. Notably, the AhR antagonist CH223191 and resveratrol have the capacity to restore the functionality of GC-1 and GC-2 cells by mitigating the effects of PCB118 and CAY10465. Based on these observations, we propose that exogenous AhR ligands PCB118 and CAY10465 promote the nuclear translocation and upregulation of AhR expression in GC-1 and GC-2 cells. This process subsequently induces mitochondrial oxidative stress, wich activates the apoptotic signaling pathway and ultimately compromises cellular viability.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"412 ","pages":"Article 111478"},"PeriodicalIF":4.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143631124","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":"Mechanisms of toxicity caused by bisphenol analogs in human in vitro cell models","authors":"Rafia Afroze Rifa,&nbsp;Macarena Gisele Rojo,&nbsp;Ramon Lavado","doi":"10.1016/j.cbi.2025.111475","DOIUrl":"10.1016/j.cbi.2025.111475","url":null,"abstract":"<div><div>Bisphenol analogs, structurally similar to bisphenol A (BPA), are widely used in various industries as a safer alternative to BPA. However, these alternatives also present risks, such as inflammation and potential connections to chronic diseases like cancer and diabetes, highlighting the need for further research into their toxicity mechanisms. Building on our previous cytotoxicity research, this study delves into the mechanisms of toxicity associated with bisphenol analogs (bisphenol AF, bisphenol AP, bisphenol E, and bisphenol P) on human <em>in vitro</em> cell models (HepaRG, Caco-2, HMC3, and HMEC-1). In this study, we assessed the impact of these compounds on key cellular stress markers: reactive oxygen species (ROS) production, mitochondrial membrane potential (ΔΨm), and mitochondrial calcium levels. Results revealed dose-dependent increases in oxidative stress and decrease in mitochondrial membrane potential (ΔΨm), with Caco-2 cells (enterocytes) exhibiting the highest sensitivity, indicating tissue-specific vulnerability. Notably, bisphenol AF, bisphenol AP and bisphenol P were identified as the most potent analogs in inducing ROS, affecting mitochondrial integrity and calcium homeostasis among all cell models. This research highlights the importance of understanding analog-specific and cell-specific responses to bisphenol compounds, providing a foundation for improved regulatory strategies to mitigate health risks associated with their exposure.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"412 ","pages":"Article 111475"},"PeriodicalIF":4.7,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630990","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":"Mechanism of arsenic regulation of mitochondrial damage and autophagy induced synaptic damage through SIRT1 and protective effect of melatonin in HT22 cell","authors":"Xiaoli Zhang ,&nbsp;Jing Wang ,&nbsp;Shuyuan Li ,&nbsp;Kun Chen ,&nbsp;Longmei Wang ,&nbsp;Chao Feng ,&nbsp;Yi Gao ,&nbsp;Xiaoyan Yan ,&nbsp;Qian Zhao ,&nbsp;Ben Li ,&nbsp;Jinping Zheng ,&nbsp;Yulan Qiu","doi":"10.1016/j.cbi.2025.111461","DOIUrl":"10.1016/j.cbi.2025.111461","url":null,"abstract":"<div><div>Arsenic (As), a widespread environmental pollutant, can induce severe neurological damage worldwide; however, the underlying mechanisms remain unclear. Sirtuin 1 (SIRT1) has been reported to exert neuroprotective effects against various neurological diseases by resisting mitochondrial damage and autophagy through deacetylation. In this study, we established a model of HT22 cells exposed to NaAsO₂ and examined the levels of mitochondrial, autophagy, and synaptic damage in HT22 cells and HT22 cells with high expression of SIRT1 (pre-treated with the agonist SRT1720) 24 h after exposure. Our results suggest that NaAsO₂ exposure induces down-regulation of SIRT1, causing mitochondrial damage and activation of autophagy, which in turn leads to synaptic damage. Notably, melatonin (Mel) intervention upregulated SIRT1 and attenuated mitochondrial damage and autophagy, restoring synaptic damage. In conclusion, the results of the present study indicate that As causes neurotoxicity by decreasing SIRT1 production, causing mitochondrial damage and activating autophagy, which provides fundamental data for further study of arsenic neurotoxicity. In addition, blocking this pathway attenuated the synaptic damage of arsenic exposure, which provides a new therapeutic avenue for arsenic neurotoxicity.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"412 ","pages":"Article 111461"},"PeriodicalIF":4.7,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626861","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":"Farnesoid X receptor regulates CYP1A1 and CYP1B1 and estradiol metabolism in mouse and human cell lines","authors":"Chanjuan Chen ,&nbsp;Pei Lin ,&nbsp;Zubao Wu ,&nbsp;Yihan Lin ,&nbsp;Meixia Huang ,&nbsp;Liangliang He ,&nbsp;Xinsheng Yao ,&nbsp;Frank J. Gonzalez ,&nbsp;Zifei Qin ,&nbsp;Zhihong Yao","doi":"10.1016/j.cbi.2025.111471","DOIUrl":"10.1016/j.cbi.2025.111471","url":null,"abstract":"<div><div>Human CYP1A1 and CYP1B1 are two important enzymes for the hydroxylation of estrogens. In this study, we aimed to investigate the potential role for <em>FXR</em> receptor in the regulation of <em>CYP1A1</em> and <em>CYP1B1</em> expressions and activities. First, pharmacokinetic analysis was conducted in male wild-type and <em>Fxr</em>^−/− mice after intraperitoneal dosing of exogenous estradiol. <em>In vitro</em> microsomal Cyp1a1 and Cyp1b1 activities were probed using their substrates estradiol, phenacetin, and melatonin. The regulatory effects of <em>FXR</em> on these two enzymes were explored using female <em>Fxr</em>^−/− mice, mouse 4T1 and human MCF-7 cell lines. As a result, <em>Fxr-</em>deficiency significantly changed the plasma concentration-time curve and exposure (AUC_0–2 h) of estradiol, and the metabolism ratios of its hydroxylated metabolites. Global deletion of <em>Fxr</em> led to significant down-regulation of <em>Cyp1a1</em> and <em>Cyp1b1</em> mRNA and protein in major organs (liver, lung, kidney, stomach, small intestine). Overexpression of <em>Fxr</em> in mouse 4T1 cells resulted in increased levels of <em>Cyp1a1</em> and <em>Cyp1b1</em> mRNA and protein, whereas <em>Fxr</em> knockdown caused down-regulation of <em>Cyp1a1</em> and <em>Cyp1b1</em> expression. In human MCF-7 cells, there was a similar regulatory trend of <em>FXR</em> towards <em>CYP1A1</em> and <em>CYP1B1</em> as well as those in mouse 4T1 cells. <em>In vitro</em> incubation assays also supported these results. Based on luciferase reporter and electrophoretic mobility shift assays, <em>Fxr</em> directly activated <em>Cyp1a1</em> and <em>Cyp1b1 via</em> their specific binding to (−488 ∼ −477 bp) and (−1475 ∼ −1460 bp) regions in their promoters, respectively. Therefore, <em>FXR</em> transcriptionally regulates the expression of <em>CYP1A1</em> and <em>CYP1B1</em>, impacting the <em>in vitro</em> metabolism and pharmacokinetics of their substrates.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"412 ","pages":"Article 111471"},"PeriodicalIF":4.7,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143598603","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 synthesis and influence of the novel bispyridinium compound LB1 on the effectiveness of the standard antidotal treatment of organophosphorus nerve agent intoxicated mice and some structure-activity considerations","authors":"Jiri Kassa ,&nbsp;Rachael E. Ambler ,&nbsp;Lynda J. Brown ,&nbsp;Jaime Cummins ,&nbsp;A. Christopher Green ,&nbsp;Christopher M. Timperley","doi":"10.1016/j.cbi.2025.111470","DOIUrl":"10.1016/j.cbi.2025.111470","url":null,"abstract":"<div><div>The design of MB327, a bispyridinium compound that ameliorates the nicotinic effects of acute organophosphorus nerve agent (NA) intoxication, followed an observation made by the German pharmacologist Klaus Schoene in the 1970s, who noted therapeutic activity in bispyridinium molecules missing the usual oxime group, CH<img>NOH. Some of these compounds protected mice against soman. One structurally related to obidoxime called HY10 had this action. Its oxime moieties were capped by <em>tert</em>-butyl groups: CH=NO<em>t</em>Bu. We modified HY10 by changing the bridge between the pyridinium units from a dimethylene ether to a trimethylene group (CH₂OCH₂ → CH₂CH₂CH₂) and prepared a novel relative of trimedoxime, called LB1, whose synthesis and stereochemistry are described. Unlike obidoxime or trimedoxime, LB1 because of its capped oxime groups, cannot directly reactivate NA inhibited acetylcholinesterase. Its antidotal activity in mice is now reported. The therapeutic efficacy of LB1, atropine alone, atropine with LB1, atropine with an oxime (HI-6, obidoxime or trimedoxime), and atropine with an oxime and LB1, was studied by determining the LD₅₀ values of the NAs soman, sarin, or tabun in mice treated with these compounds or mixtures. LB1 exceeded MB327 in toxicity and its activity was insufficient for a useful addition to the current standard antidotal treatment (protective ratio data are compared to those of MB327). Although this study produced largely negative biological results, the therapeutically beneficial mechanism of the effective bispyridinium non-oxime analogues is unclear, and has been demonstrated only <em>in vivo</em>. The present study points out directions in structural optimisation unlikely to yield the desired therapeutic outcomes and provides a literature review that could promote creative thinking for the design of widely-desirable non-oxime therapeutics for anticholinesterase inhibitors.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"413 ","pages":"Article 111470"},"PeriodicalIF":4.7,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588848","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":"Involvement of Fe(III) in the formation of immunoglobulin G-enriched protein aggregates in human plasma","authors":"Christian Saporito-Magriña ,&nbsp;María Laura Facio ,&nbsp;Lila Lopez-Montañana ,&nbsp;Guadalupe Pagano ,&nbsp;Nicole Topp ,&nbsp;Ariana Danzi ,&nbsp;Juan Ignacio Bellida ,&nbsp;Claudio Carbia ,&nbsp;Marisa Gabriela Repetto","doi":"10.1016/j.cbi.2025.111472","DOIUrl":"10.1016/j.cbi.2025.111472","url":null,"abstract":"<div><div>A small fraction of the proteins present in human plasma can be found as circulating protein aggregates. Such aggregates are formed by prone to aggregation proteins and different stimuli promote the aggregation process. Fe(III) is a redox active metal ion which also actively interacts with proteins. The aim of this work is to identify the prone to aggregation plasma proteins in presence of Fe(III) in order to outline potential targets of these circulating protein aggregates. Here we show that Fe(III) induces the formation of protein aggregates from human plasma proteins. A concentration of 100 μM Fe(III) aggregates roughly 5 % of the total plasma protein assayed. When assayed by SDS-PAGE/silver-staining, a rather homogeneous aggregate can be observed with one major protein with a molecular weight matching that of immunoglobulin G (IgG) (150k Da). Additionally, the band corresponding to albumin (66 kDa) which is the main plasma protein was absent. The identity of IgG within the aggregate and albumin depletion was corroborated by liquid chromatography-mass spectrometry. Additionally, some other proteins could be identified within the aggregate such as fibrinogen, fibronectin and Apo-B. Then, the identity of the IgG and depletion of albumin was corroborated by Western blot. It should be noted that aggregated IgGs are strong activators of inflammatory pathways involving neutrophil oxidative burst, complement cascade activation and platelet release of active amines. Therefore, the existence of a potential link between the formation of Fe(III)-induced protein aggregates and inflammation should be further explored.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"412 ","pages":"Article 111472"},"PeriodicalIF":4.7,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588845","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-Organ-on-Chip approach to study the impact of inter-organ communication on the efficacy and side effects of cancer therapy","authors":"Paweł Romanczuk ,&nbsp;Joanna Zajda ,&nbsp;Magdalena Matczuk ,&nbsp;Agnieszka Zuchowska","doi":"10.1016/j.cbi.2025.111460","DOIUrl":"10.1016/j.cbi.2025.111460","url":null,"abstract":"<div><div>Cancer is one of the pathological conditions of the human body, which, due to its tissue diversity, is not fully understood. Currently used preclinical <em>in vitro</em> cell or animal models do not reflect the complexity and functional features of the human body, including its pathological conditions such as cancer. This fact is related to poor predictions of the effectiveness of newly developed drugs. Therefore, in our work, we focused on creating a tool that allows the reproduction of important morphological and biochemical features of the tumor <em>in vivo</em>, such as three-dimensional (3D) structure, heterogeneity, the presence of extracellular matrix (ECM), and the appropriate scale (volume to surface ratio). Moreover, the presented Multi-Organ-on-Chip (MOC) tool allows us to evaluate the effects of anticancer therapy, considering hepatic metabolism (liver model) and the assessment of its side effects on a selected organ (skin model). Our research shows that incorporating multiple organ models in one <em>in vitro</em> tool affects the viability and metabolic activity of the cells that constitute them. Moreover, we have shown how important it is to consider hepatic metabolism when evaluating the therapeutic effectiveness of two selected chemotherapy drugs, 5-Fluorouracil (5-FU) and its prodrug Capecitabine (CAP).</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"413 ","pages":"Article 111460"},"PeriodicalIF":4.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588846","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":"Small molecule as potent hepatocellular carcinoma progression inhibitor through stabilizing G-quadruplex DNA to activate replication stress responded DNA damage","authors":"Fei Huang ,&nbsp;Yan Liu ,&nbsp;Jinhua Huang ,&nbsp;Dongqing He ,&nbsp;Qiong Wu ,&nbsp;Yongchang Zeng ,&nbsp;Bin Zhao ,&nbsp;Wenjie Mei","doi":"10.1016/j.cbi.2025.111469","DOIUrl":"10.1016/j.cbi.2025.111469","url":null,"abstract":"<div><div>G-quadruplex (G4) DNA, prevalent in tumor cells, offers a potential anticancer target. This study examined <strong>TA-1</strong>, a tanshinone IIA derivative, for its antitumor activity against liver cancer. We found that <strong>TA-1</strong> binds and stabilizes multiple G4 DNA,triggering DNA damage, suppressing the angiogenesis <em>in vitro</em> and <em>in vivo</em> and leading to cancer cell death. Notably, we confirmed <strong>TA-1</strong>'s inhibitory effect on liver cancer cells and explored its mechanism, which involves stabilizing G4 DNA to mediate replication-stress-dependent DNA damage. Furthermore, <strong>TA-1</strong> promotes 53BP1 expression, activating toxic NHEJ repair and leading to apoptotic cell death via the ATM-Chk2-p53 pathway. <em>In vivo</em> studies further supported these findings. In summary, <strong>TA-1</strong> is a potent <em>VEGF</em> G-quadruplex stabilizer that inhibits liver cancer progression.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"412 ","pages":"Article 111469"},"PeriodicalIF":4.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588847","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":"Identifying KDM5B as the synthetic lethal target of KMT2D-mutated osteosarcoma","authors":"Liyu Yang ,&nbsp;Jing Zhang ,&nbsp;Yiting Jiang ,&nbsp;Jiayu Zhang ,&nbsp;Zhonghua Wang ,&nbsp;Lihui Wang ,&nbsp;Xinyu Fan ,&nbsp;Gen Ba","doi":"10.1016/j.cbi.2025.111451","DOIUrl":"10.1016/j.cbi.2025.111451","url":null,"abstract":"<div><div>Osteosarcoma (OS) is a malignant bone tumor that occurs commonly in adolescents or children, previous studies have shown its complex epigenetic signature. Histone methyltransferases KMT2D loss-of-function mutation is common in various types of human cancer. Here we revealed that KMT2D loss promotes malignant phenotypes in osteosarcoma. Based on the result of epigenetic inhibitor library screening we discovered that KDM5B inhibitors selectively killed KMT2D-deficient cells. Also, the knockdown of KDM5B by shRNA could reduce cell proliferation, migration and induce apoptosis in KMT2D-KO cells, while no similar appearance was observed in wild-type cells. Furthermore, we testified the efficiency and safety of KDM5B inhibition in patient-derived xenografts (PDX) mouse models driven by KMT2D low-expressing patients. These results demonstrated KDM5B as a synthetic lethal factor of KMT2D-loss mutation. Our findings suggest a novel therapeutic strategy for treating KMT2D mutated osteosarcoma by targeting KDM5B.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"412 ","pages":"Article 111451"},"PeriodicalIF":4.7,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588844","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}