PI3K/AKT/mTOR通路促进胃癌发生发展及化疗耐药的研究进展

近年来,胃癌的抗肿瘤药物治疗取得了一定程度的进展,胃癌在全球发病率和死亡率均有所下降,但是随着胃癌患者对化疗药物耐药性的增加及肿瘤复发转移,胃癌致死率相较于其他恶性肿瘤仍居高不下。磷脂酰肌醇-3-激酶(PI3K)/蛋白激酶B(PKB/AKT)/哺乳动物雷帕霉素靶蛋白(m TOR)信号通路的异常激活与多种恶性肿瘤发生发展、促进肿瘤侵袭转移以及化疗耐药密切相关,其中就包括胃癌。本文主要就PI3K/AKT/m TOR信号通路的组成及激活过程、该通路在胃癌中的相关致癌变异以及该通路促进胃癌进展和化疗耐药的相关作用机制进行综合论述。     

PI3K/AKT/mTOR信号通路参与脊髓损伤后神经元自噬的研究进展

PI3K/AKT/mTOR信号通路是脊髓损伤后的一条经典的自噬途径,脊髓损伤后导致的神经元细胞凋亡、轴 突脱髓鞘和炎症反应等受 PI3K/AKT/mTOR 信号通路的调控,并和神经元自噬相关。介绍脊髓损伤后 PI3K/AKT/ mTOR信号通路在神经元自噬过程中的主要作用,为进一步研究脊髓损伤提供参考。     

PI3K/AKT/mTOR信号通路抑制剂在卵巢癌治疗中的研究进展

卵巢癌是女性生殖系统最致命的恶性肿瘤。目前,针对卵巢癌的规范治疗方案是肿瘤细胞减灭术辅以紫杉醇/铂类联合化疗,然而大多数晚期卵巢癌患者最终因对化疗药物耐药而复发。PI3K/AKT/m TOR信号通路作为一条重要的原癌基因通路,在卵巢癌中激活并在卵巢癌的增殖、侵袭、细胞周期进程、血管形成及耐药中发挥着重要的作用,抑制该通路是卵巢癌的一个潜在治疗方法。对PI3K/AKT/m TOR信号通路抑制剂在卵巢癌治疗中的研究进展进行综述。     

PI3K/AKT/mTOR信号通路抑制剂在宫颈癌治疗中的研究进展

宫颈癌是女性常见恶性肿瘤之一。针对局部晚期及复发转移的宫颈癌患者尚未有令人满意的治疗手段,因此探索和发展更有效的治疗方案具有重要的意义。PI3K/AKT/m TOR信号通路在人类子宫颈癌细胞的增殖、分化和凋亡中具有重要的调节作用,有希望成为开发宫颈癌治疗药物的新型靶标。综述了近年来PI3K/AKT/m TOR信号通路的单一及双重靶点抑制剂针对宫颈癌的临床前及临床研究情况,包括PI3K抑制剂(wortmannin、LY294002、吲哚-3-甲醇)、AKT抑制剂(SC-66、MK-2206、木黄酮、冬凌草甲素和雷公藤)、m TOR抑制剂(替西罗莫司和依维莫司)及双重靶点抑制剂(GSK2126458、BEZ235、BGT226、PF04691502、GDC-0980和PKI-587)等。     

黄酮类新化合物LFG-500通过调控MAPK和AKT/mTOR信号通路抑制人乳腺癌MCF-7细胞增殖

目的 考察黄酮类新化合物LFG-500对人乳腺癌MCF-7细胞的生长抑制作用,并初步探讨其抑制细胞增殖的作用机制。方法 体外培养MCF-7细胞,实验设置空白对照组,以及浓度为10、20、30μM的LFG-500处理组,处理细胞24 h。通过平板克隆形成实验检测LFG-500对细胞的增殖能力的抑制作用;利用Western blot实验检测LFG-500对MCF-7细胞内MAPK信号通路关键蛋白ERK/p-ERK、JNK/p-JNK、p38/p-p38及AKT/mTOR信号通路核心蛋白AKT/p-AKT、mTOR/p-mTOR的调节作用。结果 平板克隆形成实验结果显示,与对照组相比,LFG-500中、高剂量组MCF-7细胞增殖明显受到抑制（P <0.01）;Western blot结果显示,LFG-500可上调MCF-7细胞中MAPK信号通路核心蛋白p-JNK和p-p38的表达,下调p-ERK的表达（P <0.05）。此外,LFG-500也可抑制AKT/mTOR信号通路的核心蛋白p-AKT和p-mTOR的表达水平（P <0.05）。结论 LFG-500可能通过调控MAPK...     

TRESK介导mTOR信号通路对大鼠脊髓神经元细胞凋亡的影响

目的 探究双孔钾离子通道(TRESK)介导的mTOR信号通路对大鼠脊髓神经元细胞凋亡的影响.方法 培养100例SD大鼠的脊髓原代神经元细胞,分为4组,每组各25例,A组采用TRESK siRNA、mTOR特异性抑制剂、谷氨酸处理,B组采用mTOR特异性抑制剂、谷氨酸处理,C组不进行任何处理,D组仅进行谷氨酸处理.对比各...     

雷公藤红素通过PI3K/AKT/mTOR信号通路对胃癌MFC细胞增殖和凋亡的影响

目的研究雷公藤红素对胃癌MFC细胞内PI3K/AKT/mTOR信号通路的影响及其对胃癌MFC细胞增殖的抑制和促凋亡作用机制。方法分别设置对照组和雷公藤红素低、中、高剂量(5、10、20 mmol/L)组,采用MTT法检测雷公藤红素对胃癌MFC细胞增殖的影响;采用流式细胞技术检测雷公藤红素对胃癌MFC细胞周期的影响及MFC细胞凋亡的情况;Western blotting检测雷公藤红素对胃癌MFC细胞内凋亡相关蛋白Bax、Bcl-2和PI3K、AKT和mTOR蛋白表达的影响;实时定量PCR检测雷公藤红素对胃癌MFC细胞内PI3K、AKT和mTORm RNA表达的影响。结果与对照组比较,雷公藤红素能够呈剂量相关性地显著抑制胃癌MFC细胞的增殖(P0.05);与对照组比较,雷公藤红素能够呈剂量相关性地显著引起MFC细胞G2/M期阻滞(P0.05);与对照组比较,雷公藤红素能够呈剂量相关性地显著促进MFC细胞的凋亡(P0.05);与对照组比较,雷公藤红素能够呈剂量相关性地显著抑制MFC细胞内抗凋亡蛋白Bcl-2蛋白和PI3K、AKT、mTOR蛋白的表达(P0.05),显著促进MFC细胞内促凋亡蛋白Bax的表达(P0.05);与对照组比较,雷公藤红素能够呈剂量相关性地显著抑制MFC细胞内PI3K、AKT和mTORm RNA的表达(P0.05)。结论雷公藤红素能够抑制胃癌MFC细胞的增殖并促进胃癌MFC细胞凋亡,其作用机制可能是通过抑制胃癌MFC细胞内PI3K/AKT/mTOR信号通路中PI3K、AKT、mTOR等蛋白的表达而抑制胃癌MFC细胞的增殖,进而促进胃癌MFC细胞内促凋亡蛋白Bax的表达,同时抑制抗凋亡蛋白Bcl-2的表达,从而促进胃癌MFC细胞凋亡。     

红景天苷通过AKT/mTOR信号通路对结肠癌细胞SW480增殖、凋亡和裸鼠移植瘤生长的影响

目的 探究红景天苷(salidroside, SAL)对结肠癌细胞SW480增殖、凋亡和裸鼠移植瘤生长的影响。方法 采用0、25、50、100μmol·L^-1剂量红景天苷处理SW480细胞,将细胞随机分为4组：SAL 0μmol·L^-1组、SAL 25μmol·L^-1组、SAL 50μmol·L^-1组和SAL 100μmol·L^-1组。克隆形成实验检测细胞克隆形成率;流式细胞仪检测细胞凋亡;Western blot检测Ki67、PCNA、Caspase-3、Caspase-9、PI3K、p-PI3K、AKT、p-AKT、mTOR、p-mTOR蛋白表达水平。建立结肠癌裸鼠移植瘤模型,裸鼠随机分为2组：Control组和Salidroside 50 mg·kg^-1组,检测裸鼠肿瘤重量,TUNEL染色检测裸鼠肿瘤细胞凋亡率,免疫组化染色检测Ki67、Caspase-3阳性细胞数。结果 体外实验中,与SAL 0μmol·L^-1组相比较,SAL...     

虎杖苷对慢性阻塞性肺疾病大鼠PI3K/AKT/mTOR通路以及气道炎症的影响

目的 构建慢性阻塞性肺疾病（COPD）大鼠模型,探讨虎杖苷对COPD大鼠PI3K/AKT/mTOR通路以及气道炎症的影响。方法 100只Wistar大鼠随机分为对照组、模型组、地塞米松（0.2 mg/kg,阳性药）组和虎杖苷低、高剂量（30、60 mg/kg）组,每组20只。除对照组外,其他组熏香烟加气管注射内毒素法制备COPD模型,COPD造模前1 d开始ig给药,每天1次,持续30 d。ELISA法检测支气管肺泡灌洗液（BALF）中肿瘤坏死因子（TNF）-α和白细胞介素（IL）-6水平;RSE3020肺功能检测仪测定用力肺活量（FVC）、第1秒用力呼气容积（FEV₁）、呼气峰流速（PEF）;取肺组织4%甲醛固定后制作切片,HE染色,并进行肺组织损伤病理评分;Western blotting检测肺组织PI3K、AKT、mTOR蛋白表达。结果 虎杖苷高、低剂量组大鼠BALF中TNF-α和IL-6表达水平、肺组织损伤病理评分以及PI3K、AKT和mTOR蛋白表达均显著低于模型组（P<0.01）;虎杖苷高、低剂量组大鼠FVC、FEV1、PEF肺功能指标显著高于模型组（P<0.01）。结论 虎杖苷可以抑制COPD大鼠PI3K/AKT/mTOR通路,抑制气道炎症,发挥肺损伤保护作用。     

血府逐瘀汤通过PI3K/AKT/mTOR信号通路影响低氧性肺动脉高压大鼠肺血管重构的研究

目的 探讨血府逐瘀汤对低氧性肺动脉高压（hypoxic pulmonary hypertension,HPH）大鼠肺血管重构的影响及其相关机制。方法 40只♂ SD大鼠随机分为正常对照组、模型组、血府逐瘀汤组、NVP-BEZ235组、药物联合组,每组8只。采用低压低氧法建立大鼠HPH模型。HE染色观察大鼠肺小动脉病理改变,Masson染色观察肺小动脉胶原纤维含量,免疫组化检测肺小动脉增殖细胞核抗原（proliferating cell nuclear antigen,PCNA）的表达,Western blotting测定肺组织p-AKT、AKT、p-mTOR、mTOR和PCNA的表达。结果 与正常对照组比较,模型组大鼠肺小动脉血管壁增厚、管腔变窄,胶原纤维含量显著增加（P<0.01）,PCNA、p-AKT、p-mTOR表达增加（P<0.05或P<0.01）;与模型组比较,各药物治疗组大鼠肺小动脉病理改变不同程度减轻,胶原纤维含量显著减少（P<0.01）,PCNA、p-AKT、p-mTOR表达降低（P<0.05或P<0.01）;药物联合组与血府逐瘀汤组相比,胶原纤维含量减少（P<0.05）,PCNA、p-AKT、p-mTOR表达降低（P<0.01）。结论 血府逐瘀汤能有效减轻HPH大鼠肺血管重构,减少血管壁胶原纤维含量以及PCNA的表达,其机制可能与抑制PI3K/AKT/mTOR信号通路活化相关。     

水仙环素活化AKT/mTOR通路减轻高氧诱导新生大鼠急性肺损伤

目的：探讨水仙环素对高氧诱导新生大鼠急性肺损伤的影响及其机制。方法：取足月新生Wistar大鼠40只,随机分为常氧组（21% O2）、常氧+水仙环素组、高氧组（85% O2）、高氧+水仙环素组,每组10只。各组大鼠于不同含氧量条件下暴露7 d,另取足月新生大鼠50只,随机分为常氧组、高氧组、高氧+水仙环素组、高氧+水仙环素+蛋白激酶B（AKT）抑制剂组及高氧+水仙环素+雷帕霉素组,每组10只。各药物组于出生后0、2、4、6 d时分别腹腔注射1 mg/kg水仙环素、1mg/kg AKT抑制剂和4mg/kg雷帕霉素,比较各组大鼠肺损伤、促炎细胞因子、纤维化及肺组织细胞凋亡水平。结果：与常氧组比较,高氧组大鼠体质量、肺组织B淋巴细胞瘤-2基因/Bcl-2相关X蛋白（Bcl-2/Bax）水平明显降低,支气管肺泡灌洗液（BALF）中细胞总数、总蛋白及肺组织湿干质量、BALF与血清中肿瘤坏死因子α（TNF-α）、白细胞介素-1β（IL-1β）、单核细胞趋化因子（MCP-1）、IL-6含量、肺组织α平滑肌动蛋白（α-SMA）、波形蛋白及胶原蛋白Ⅰ表达、肺组织细胞凋亡率、原代肺成纤维细胞凋亡率、磷酸化蛋白激酶B（p-AKT）/AKT、磷酸化雷帕霉素靶蛋白（p-mTOR）/mTOR升高（P<0.05）;常氧组与常氧+水仙环素组上述指标比较差异无统计学意义（P>0.05）。与高氧组比较,高氧+水仙环素组体质量、肺组织Bcl-2/Bax水平升高,BALF中细胞总数、总蛋白及肺组织湿/干质量、BALF与血清中TNF-α、IL-1β、MCP-1、IL-6含量、肺组织α-SMA、波形蛋白及胶原蛋白Ⅰ表达、肺组织细胞凋亡率、原代肺成纤维细胞凋亡率、p-AKT/AKT、p-mTOR/mTOR降低（P<0.05）。与高氧+水仙环素组比较,高氧+水仙环素+AKT抑制剂组TNF-α、IL-1β水平升高（P<0.05）,高氧+水仙环素+雷帕霉素组TNF-α、IL-1β、胶原蛋白Ⅰ表达升高,Bcl-2/Bax水平明显降低（P<0.05）。结论：水仙环素可保护新生大鼠高氧肺损伤,其机制可能与水仙环素活化AKT/mTOR信号通路,改善炎症反应、减缓肺纤维化程度、抑制肺组织细胞的凋亡有关     

华蟾素对肺癌大鼠PI3K/AKT信号通路的抑制作用

目的探讨华蟾素对肺癌模型大鼠肿瘤标志物、免疫功能及PI3K/AKT信号通路蛋白表达的影响。方法将80只Wistar大鼠随机分为对照组、模型组、华蟾素组和环磷酰胺组,每组20只,采用气管内灌注致癌碘油液建立肺癌大鼠模型。分别于第4,8周比较组织病理形态、血清肿瘤标志物癌胚抗原(CEA)、糖类抗原-125(CA125)和神经元特异性烯醇化酶(NSE)水平,T细胞亚群CD3^+、CD4^+、CD8^+细胞及NKT细胞含量,AKT-1、Cyclin D1、NF-κB mRNA表达,PI3K、p-AKT蛋白表达。结果华蟾素组大鼠体质量先减少,3周后逐渐增加,环磷酰胺组大鼠的体质量先减少,4周后有所增加。与模型组比较,华蟾素组和环磷酰胺组的肿瘤体积、质量显著降低,抑瘤率显著增加(P<0.05);肺组织肿胀不明显,肺泡囊及上皮细胞结构基本清晰;华蟾素组和环磷酰胺组血清CEA、CA125、NSE水平显著降低,AKT-1、Cyclin D1和NF-κB mRNA表达显著降低,PI3K、p-AKT蛋白表达显著降低;华蟾素组CD3^+和CD4^+细胞含量显著升高,CD8^+和NKT细胞含量显著降低,且第8周与第4周相比,差异具有统计学意义(P<0.05)。结论华蟾素可增加肺癌模型大鼠体质量,降低肿瘤体积和质量,增加抑瘤率,改善肿瘤标志物和免疫功能,其机制可能与降低AKT-1、Cyclin D1、NF-κB mRNA水平和PI3K、p-AKT蛋白表达有关。     

miR-10b 通过mTOR/P70S6K 信号通路对宫颈癌大鼠的作用机制研究

目的探讨miR-10b通过mTOR/P70S6K信号通路对宫颈癌大鼠的作用机制。方法采用人宫颈癌HeLa细胞株构建宫颈癌大鼠模型,分为Gg组(宫颈癌大鼠)、Gm组(注射miR-10b-mimics)、Gi组(注射miR-10b-inhibitions)。采用HE染色观察癌组织变化,Western blotting、RT-PCR检测mTOR/P70S6K的mRNA和蛋白表达水平,Transwell检测HeLa细胞的侵袭能力。结果Gg组肿瘤组织出现丰富的血供,界限分明,切面呈鱼肉状,肿瘤细胞大小较为均等;Gm组肿瘤组织中有大量纤维血管形成,肿瘤细胞大小不等,胞浆着色较深;Gi组肿瘤组织中纤维血管较少,胞浆着色稍浅。Western blotting结果显示,mTOR/P70S6K蛋白表达水平为Gm组Gg组>Gm组(P<0.05),miR-10b mRNA水平为Gi组Gg组>Gm组(P<0.05)。结论miR-10b过表达可激活mTOR蛋白,增加P70S6K活性,抑制宫颈癌细胞的增殖和迁移,有望成为宫颈癌治疗的新靶点。     

索马鲁肽对早期2型糖尿病心肌病大鼠mTOR信号通路的干预作用

目的 探讨索马鲁肽对糖尿病心肌病大鼠心肌组织哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin,mTOR）信号通路表达的干预作用。方法 高脂饮食5周后,腹腔注射链脲佐菌素建立2型糖尿病大鼠模型,实验将大鼠分为正常对照组、糖尿病2周、4周模型组和索马鲁肽组,索马鲁肽组在造模成功后给予索马鲁肽灌胃处理。4周后,各组动物进行血清学检测,包括空腹血糖、总胆固醇、甘油三酯、高密度脂蛋白（HDL-C）、低密度脂蛋白（LDL-C）、空腹胰岛素,超声心动图检测心功能相关指标,Western blot检测心肌mTOR、p-mTOR、S6K1、Atg5和P62蛋白表达变化。结果 与正常对照组比较,2型糖尿病大鼠2周和4周模型血清中总胆固醇、甘油三酯、LDL-C水平显著升高,HDL-C水平显著降低;索马鲁肽组空腹血糖值趋于正常,HDL-C水平升高显著（P<0.05）,LDL-C水平显著降低（P<0.01）。相对于正常对照组,糖尿病模型组大鼠心肌组织中mTOR、p-mTOR、S6K1的表达与正常对照组相比随时间持续增加（P<0.01）,自噬相关蛋白Atg5和P62表达也显著增加（P<0.05）,而索马鲁肽组均显示出降低趋势。结论 在早期糖尿病心肌病的发生发展过程中,索马鲁肽对mTOR信号通路具有抑制作用,能降低心肌细胞自噬损伤的发生。     

MC-LR Aggravates Liver Lipid Metabolism Disorders in Obese Mice Fed a High-Fat Diet via PI3K/AKT/mTOR/SREBP1 Signaling Pathway

Obesity, a metabolic disease caused by excessive fat accumulation in the body, has attracted worldwide attention. Microcystin-LR (MC-LR) is a hepatotoxic cyanotoxin which has been reportedly to cause lipid metabolism disorder. In this study, C57BL/6J mice were fed a high-fat diet (HFD) for eight weeks to build obese an animal model, and subsequently, the obese mice were fed MC-LR for another eight weeks, and we aimed to determine how MC-LR exposure affects the liver lipid metabolism in high-fat-diet-induced obese mice. The results show that MC-LR increased the obese mice serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), indicating damaged liver function. The lipid parameters include serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and liver TG, which were all increased, whilst the high-density lipoprotein cholesterol (HDL-c) was decreased. Furthermore, after MC-LR treatment, histopathological observation revealed that the number of red lipid droplets increased, and that steatosis was more severe in the obese mice. In addition, the lipid synthesis-related genes were increased and the fatty acid β-oxidation-related genes were decreased in the obese mice after MC-LR exposure. Meanwhile, the protein expression levels of phosphorylation phosphatidylinositol 3-kinase (p-PI3K), phosphorylation protein kinase B (p-AKT), phosphorylation mammalian target of rapamycin (p-mTOR), and sterol regulatory element binding protein 1c (SREBP1-c) were increased; similarly, the p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR, and SREBP1/β-actin were significantly up-regulated in obese mice after being exposed to MC-LR, and the activated PI3K/AKT/mTOR/SREBP1 signaling pathway. In addition, MC-LR exposure reduced the activity of superoxide dismutase (SOD) and increased the level of malondialdehyde (MDA) in the obese mice’s serum. In summary, the MC-LR could aggravate the HFD-induced obese mice liver lipid metabolism disorder by activating the PI3K/AKT/mTOR/SREBP1 signaling pathway to hepatocytes, increasing the SREBP1-c-regulated key enzymes for lipid synthesis, and blocking fatty acid β-oxidation.     

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen. Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual- and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignancies, the agents that are used to target this pathway, and the results of preclinical and clinical trials, using those agents in childhood hematologic cancers.     

Zearalenone Induces Apoptosis in Porcine Endometrial Stromal Cells through JNK Signaling Pathway Based on Endoplasmic Reticulum Stress

Zearalenone (ZEA) is an estrogen-like mycotoxin characterized mainly by reproductive toxicity, to which pigs are particularly sensitive. The aim of this study was to investigate the molecular mechanism of ZEA-induced apoptosis in porcine endometrial stromal cells (ESCs) by activating the JNK signaling pathway through endoplasmic reticulum stress (ERS). In this study, ESCs were exposed to ZEA, with the ERS inhibitor sodium 4-Phenylbutyrate (4-PBA) as a reference. The results showed that ZEA could damage cell structures, induce endoplasmic reticulum swelling and fragmentation, and decreased the ratio of live cells to dead cells significantly. In addition, ZEA could increase reactive oxygen species and Ca²⁺ levels; upregulate the expression of GRP78, CHOP, PERK, ASK1 and JNK; activate JNK phosphorylation and its high expression in the nucleus; upregulate the expression Caspase 3 and Caspase 9; and increase the Bax/Bcl-2 ratio, resulting in increased apoptosis. After 3 h of 4-PBA-pretreatment, ZEA was added for mixed culture, which showed that the inhibition of ERS could reduce the cytotoxicity of ZEA toward ESCs. Compared with the ZEA group, ERS inhibition increased cell viability; downregulated the expression of GRP78, CHOP, PERK, ASK1 and JNK; and decreased the nuclear level of p-JNK. The Bax/Bcl-2 ratio and the expression of Caspase 3 and Caspase 9 were downregulated, significantly alleviating apoptosis. These results demonstrate that ZEA can alter the morphology of ESCs, destroy their ultrastructure, and activate the JNK signaling via the ERS pathway, leading to apoptosis.