Chemico-Biological Interactions最新文献

{"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}

{"title":"The anti-Alzheimer's disease effects of ganoderic acid A by inhibiting ferroptosis-lipid peroxidation via activation of the NRF2/SLC7A11/GPX4 signaling pathway","authors":"Qingyang Lu ,&nbsp;Nan Shao ,&nbsp;Ziyi Fang ,&nbsp;Zhaorong Ouyang ,&nbsp;Yiran Shen ,&nbsp;Ruiling Yang ,&nbsp;Houli Liu ,&nbsp;Biao Cai ,&nbsp;Tao Wei","doi":"10.1016/j.cbi.2025.111459","DOIUrl":"10.1016/j.cbi.2025.111459","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a degenerative disease of the central nervous system, characterized by a gradual decline in cognitive and memory abilities, social disorders, and behavioral abnormalities. Ferroptosis, an iron-dependent type of programmed cell death, is closely associated with the pathogenesis of AD. Ferroptosis is characterized by the accumulation of iron within cells, leading to increased oxidative stress, and ultimately lipid peroxidation and cell death. Ganoderic acid A (GAA), one of the major pharmacologically active components in <em>Ganoderma lucidum</em>, exhibits an excellent neuroprotective effect against AD. However, it is unclear whether GAA improves the symptoms of AD by inhibiting ferroptosis. This study investigated the anti-AD effects of GAA through both <em>in vivo</em> and <em>in vitro</em> experiments, and determined its molecular mechanism from the perspective of ferroptosis modulation. The results showed that GAA administration attenuated hippocampal neuronal loss, improved mitochondrial ultrastructure, and enhanced the memory and learning ability of the AD mice. <em>In vitro</em> assays suggested that GAA effectively protected HT22 AD cells against ferroptosis-related morphological damage, enhanced their antioxidant capacity, maintained their iron metabolism, and reduced mitochondrial dysfunction. Moreover, the immunofluorescence and western blotting results showed that the levels of NFE2 like bZIP transcription factor 2 (NRF2), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11) both in the hippocampus of APP/PS1 mice and amyloid beta (Aβ)_25-35-induced HT22 AD cells were markedly enhanced after GAA administration. In summary, these results revealed that GAA improves AD by activating on the NRF2/SLC7A11/GPX4 axis to inhibit ferroptosis-lipid peroxidation.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"412 ","pages":"Article 111459"},"PeriodicalIF":4.7,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143576906","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":"Chlorpyrifos-oxon results in autophagic flux dysfunction contributing to neuronal apoptosis via a ROS/AMPK/CHOP activation pathway","authors":"Jui-Ming Liu ,&nbsp;Kuan-I Lee ,&nbsp;Chin-Chuan Su ,&nbsp;Kai-Min Fang ,&nbsp;Shing-Hwa Liu ,&nbsp;Shih-Chang Fu ,&nbsp;Chun-Ying Kuo ,&nbsp;Kai-Chih Chang ,&nbsp;Jun-An Ke ,&nbsp;Ya-Wen Chen ,&nbsp;Ching-Yao Yang ,&nbsp;Chun-Fa Huang","doi":"10.1016/j.cbi.2025.111452","DOIUrl":"10.1016/j.cbi.2025.111452","url":null,"abstract":"<div><div>Chlorpyrifos (CPF) is a widely used organophosphate (OP) pesticide in agriculture and sanitation, known to elicit neurotoxic effects. Chlorpyrifos-oxon (CPO), a metabolite of CPF, is the primary neurotoxic agent, yet its mechanisms are less understood. In this study, we investigated the effects and underlying mechanisms of CPO-induced neurotoxicity. CPO exposure significantly induced cytotoxicity in Neuro-2a cells, alongside the activation of apoptosis, as evidenced by an increase in the apoptotic cell population, caspase-3 activity, and cleavage of caspaspe-3, -7, and PARP proteins. Furthermore, defective autophagy was observed in CPO-treated Neuro-2a cells, indicated by increased expression of Beclin-1, Atg5, LC3-II, and p62 proteins. 3-MA, an autophagy inhibitor, suppressed CPO-activated LC3-II and apoptotic marker proteins expression, but not p62. In contrast, chloroquine and bafilomycin A1, autophagic flux inhibitors, potentiated the CPO-induced elevation of LC3-II, p62, and cleaved caspase-3 and -7 protein levels. CPO exposure also upregulated CHOP protein expression. Transfection with CHOP-specific siRNA markedly reduced CHOP protein expression, autophagic flux dysfunction, and apoptosis. Additionally, CPO exposure significantly increased AMPKα phosphorylation and reactive oxygen species (ROS) generation. Antioxidant <em>N</em>-acetylcysteine (NAC), but not the AMPK inhibitor Compound C, effectively attenuated the CPO-induced ROS generation in neuronal cells, which was accompanied by the prevention of AMPKα activation, downstream CHOP expression, autophagic flux dysfunction, and apoptosis. Collectively, these findings suggest that CPO-induced neurotoxicity arises from autophagic flux dysfunction, contributing to apoptosis via the ROS-activated AMPK pathway, which regulates CHOP expression, ultimately leading to neuronal cell death. Targeting the ROS/AMPK/CHOP axis may offer a promising intervention to against CPO-induced neurotoxicity.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"412 ","pages":"Article 111452"},"PeriodicalIF":4.7,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143574925","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":"Metabolomic insights into methamphetamine exposure: 1H-NMR-based urinary biomarker identification and pathway disruption","authors":"Varat Budsayapanpong ,&nbsp;Yutti Amornlertwatana ,&nbsp;Giatgong Konguthaithip ,&nbsp;Somlada Watcharakhom ,&nbsp;Kanicnan Intui ,&nbsp;Jatuporn Chaichana ,&nbsp;Manee Khamenkhetkarn ,&nbsp;Churdsak Jaikang","doi":"10.1016/j.cbi.2025.111449","DOIUrl":"10.1016/j.cbi.2025.111449","url":null,"abstract":"","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"412 ","pages":"Article 111449"},"PeriodicalIF":4.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538245","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":"Palmitic acid-induced insulin resistance triggers granulosa cell senescence by disruption of the UPRmt/mitophagy/lysosome axis","authors":"Yuan Tian ,&nbsp;Pengge Pan ,&nbsp;Xiaoqiang Luo ,&nbsp;Yaqi Sun ,&nbsp;Xintong Yang ,&nbsp;Hui Gao ,&nbsp;Yanzhou Yang","doi":"10.1016/j.cbi.2025.111450","DOIUrl":"10.1016/j.cbi.2025.111450","url":null,"abstract":"<div><div>Insulin resistance (IR) is the main pathological feature of polycystic ovary syndrome (PCOS), but the adverse impacts of IR on ovary and granulosa cells (GCs) are unknown. Therefore, the role of palmitic acid (PA) induced IR in GCs, and a mitochondrial proteostasis and mitochondrial homeostasis control system, the mitochondrial unfolded protein response (UPR^mt)/mitophagy/lysosome axis were investigated to uncover the side effect and the mechanism of IR on GCs. Our results revealed that IR in GC was successfully constructed by 100 μM PA treatment accompanied with cell senescence. In addition, mitochondrial function was impaired by IR-induced GC senescence accompanied by significantly increased reactive oxygen species (ROS) and decreased mitochondrial membrane potential, and mitochondrial proteostasis was impaired by a dysfunctional UPR^mt and increased protein aggregation, leading to more unfolded and misfolded proteins accumulating in mitochondria. Mitochondrial homeostasis was maintained by the mitophagy/lysosome degradation system, although mitophagy was significantly increased, lysosomes were damaged; hence, malfunctional mitochondria were not cleared by the mitophagy/lysosome degradation system, more ROS were produced by malfunctional mitochondria. Therefore, accelerated GC senescence was triggered by excessive ROS, and reversed by the mitophagy inhibitor cyclosporin A (CsA) accompanied with reduced IR. Additionally, the mice were administered with PA, and results revealed that the accelerated ovarian aging was caused by PA, which might be attributed to GC senescence. In conclusion, GC senescence was triggered in PA-induced IR by disruption of the UPR^mt/mitophagy/lysosome axis, and IR induced GC senescence was reversed by the CsA.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"411 ","pages":"Article 111450"},"PeriodicalIF":4.7,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143529402","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}