STAT家族蛋白：細(xì)胞命運(yùn)的“指揮官”，疾病發(fā)展的關(guān)鍵推手

1. STAT家族簡(jiǎn)介

信號(hào)傳導(dǎo)子和轉(zhuǎn)錄激活子（STAT）家族是一類(lèi)關(guān)鍵的細(xì)胞內(nèi)蛋白，充當(dāng)細(xì)胞質(zhì)信號(hào)傳導(dǎo)分子和核轉(zhuǎn)錄因子的雙重角色。當(dāng)細(xì)胞因子、生長(zhǎng)因子或激素等信號(hào)分子與細(xì)胞表面受體結(jié)合后，STATs就會(huì)被激活。激活的STATs形成二聚體，轉(zhuǎn)運(yùn)到細(xì)胞核內(nèi)，直接結(jié)合特定DNA序列，調(diào)控靶基因的表達(dá)，從而介導(dǎo)細(xì)胞增殖、分化、存活、免疫應(yīng)答和炎癥等多種重要的細(xì)胞過(guò)程。

1.1 STAT家族結(jié)構(gòu)

STATs是JAKs下游的信號(hào)分子。哺乳動(dòng)物中有7個(gè)STAT家族成員（STAT1、STAT2、STAT3、STAT4、STAT5A、STAT5B和STAT6），它們?cè)诟鞣N生理和病理過(guò)程中扮演著獨(dú)特且有時(shí)重疊的角色。STATs由750-900個(gè)氨基酸組成。從N端到C端，由N端結(jié)構(gòu)域、卷曲螺旋結(jié)構(gòu)域、DNA結(jié)合結(jié)構(gòu)域、連接結(jié)構(gòu)域、SH2結(jié)構(gòu)域和轉(zhuǎn)錄激活結(jié)構(gòu)域組成。六個(gè)結(jié)構(gòu)域調(diào)節(jié)STATs的不同功能：（1）N端結(jié)構(gòu)域促進(jìn)STATs二聚體的形成，從而使其能夠與轉(zhuǎn)錄因子結(jié)合；（2）卷曲螺旋結(jié)構(gòu)域與調(diào)節(jié)蛋白有關(guān)，并參與STATs核導(dǎo)入和導(dǎo)出過(guò)程的控制；（3）DNA結(jié)合結(jié)構(gòu)域可以識(shí)別并結(jié)合靶基因調(diào)控區(qū)中的DNA序列；（4）連接結(jié)構(gòu)域在結(jié)構(gòu)上將DNA結(jié)合結(jié)構(gòu)域連接到SH2結(jié)構(gòu)域；（5）STATs的SH2結(jié)構(gòu)域在家族中非常保守，主要功能是識(shí)別細(xì)胞因子受體的磷酸酪氨酸基序；（6）轉(zhuǎn)錄激活結(jié)構(gòu)域?qū)τ?/span>DNA轉(zhuǎn)錄元件和通過(guò)保守的絲氨酸磷酸化位點(diǎn)募集共激活因子和調(diào)節(jié)轉(zhuǎn)錄至關(guān)重要。

圖1 STAT家族的結(jié)構(gòu)、磷酸化位點(diǎn)、活性和非活性形式二聚體

（圖片源于《Protein Science》^[1]）

1.2 STATs激活方式

STATs在JAKs下游傳遞I/II型細(xì)胞因子信號(hào)。非活性細(xì)胞質(zhì)STATs主要以單體或預(yù)先形成的二聚體形式存在。激活的JAKs導(dǎo)致結(jié)合受體的酪氨酸磷酸化，形成STATs的?？课稽c(diǎn)。在這個(gè)?？课稽c(diǎn)，JAKs磷酸化STATs，然后STATs與受體解離，并通過(guò)SH2結(jié)構(gòu)域-磷酸化酪氨酸相互作用形成同型二聚體或異二聚體。激活后，STATs二聚體形成胡桃?jiàn)A狀結(jié)構(gòu)。高度保守的SH2結(jié)構(gòu)域形成了該結(jié)構(gòu)的鉸鏈，是大多數(shù)STATs抑制劑的靶標(biāo)。然后，這些二聚體轉(zhuǎn)移到細(xì)胞核中，誘導(dǎo)啟動(dòng)子含有適當(dāng)STATs結(jié)合位點(diǎn)的基因轉(zhuǎn)錄。細(xì)胞核中磷酸酶對(duì)STATs的去磷酸化使它們能夠穿梭回細(xì)胞質(zhì)中，進(jìn)行下一個(gè)輪次的激活。

圖2 細(xì)胞因子誘導(dǎo)的JAK/STAT通路信號(hào)級(jí)聯(lián)示意圖

（圖片源于《Protein Science》^[1]）

2. STATs與腫瘤的相關(guān)研究

越來(lái)越多的證據(jù)表明，STATs激活與腫瘤進(jìn)展有關(guān)。多項(xiàng)研究表明，STAT1、STAT2、STAT3、STAT4、STAT5、STAT6在白血病、乳腺癌、前列腺癌、結(jié)直腸癌、肝癌、腎細(xì)胞癌（RCC）等腫瘤中激活^[2-9]。高STATs磷酸化水平與更高的復(fù)發(fā)風(fēng)險(xiǎn)、腫瘤晚期、靜脈浸潤(rùn)、多發(fā)性腫瘤結(jié)節(jié)相關(guān)，提示患者預(yù)后不良^{[4,5,7,10-14]}。STATs的激活驅(qū)動(dòng)腫瘤的上皮間質(zhì)轉(zhuǎn)化（EMT）并增強(qiáng)侵襲性和遷移性^[3,7,15-17]。STAT1是HPV陰性頭頸部鱗狀細(xì)胞癌（HNSCC）小鼠模型中放射耐藥的介質(zhì)^[18]。下調(diào)STAT1表達(dá)可顯著提高RCC細(xì)胞系的放射敏感性^[8]。STAT5a通過(guò)上調(diào)ABCB1的轉(zhuǎn)錄賦予乳腺癌化療耐藥性^[19]。阻斷STAT3和STAT5磷酸化并誘導(dǎo)其降解，可選擇性地誘導(dǎo)原代T細(xì)胞幼淋巴細(xì)胞白血?。?/span>T-PLL）中的細(xì)胞死亡^[20]。STAT3敲低促進(jìn)索拉非尼誘導(dǎo)的細(xì)胞凋亡，刺激樹(shù)突狀細(xì)胞中的cGAS-STING信號(hào)通路，從而增強(qiáng)了CD8 T和NK細(xì)胞的抗腫瘤功能^[21]。STAT3或STAT5的靶向抑制可誘導(dǎo)骨肉瘤細(xì)胞周期停滯和凋亡，并顯著抑制小鼠模型中異種移植物的生長(zhǎng)^[22,23]。這些發(fā)現(xiàn)強(qiáng)調(diào)了靶向抑制STATs可能是一種有前景的腫瘤治療方法。

圖3 JPX-1244直接靶向STAT3和STAT5，影響蛋白質(zhì)磷酸化和穩(wěn)定性

（圖片源于《Leukemia》^[20]）

3. STATs與自身免疫疾病的相關(guān)研究

STATs是細(xì)胞因子信號(hào)通路的核心轉(zhuǎn)錄因子家族，其異常激活與多種自身免疫性疾病的發(fā)病機(jī)制密切相關(guān)。在類(lèi)風(fēng)濕性關(guān)節(jié)炎（RA）、系統(tǒng)性紅斑狼瘡（SLE）、銀屑病、干燥綜合征、克羅恩?。?/span>CD）和潰瘍性結(jié)腸炎（UC）等多種疾病中，STAT1、STAT2、STAT3、STAT5、STAT6總蛋白及其磷酸化形式的水平升高^[24-36]。STAT4基因內(nèi)的多個(gè)SNP與自身免疫性疾病有很強(qiáng)的遺傳關(guān)聯(lián)，與疾病易感性和發(fā)展顯著相關(guān)^[37-39]。抑制STAT1或STAT3可改善RA動(dòng)物模型中的關(guān)節(jié)炎癥和關(guān)節(jié)破壞，顯著抑制疾病進(jìn)展^[40,41]。STAT6敲除可減輕小鼠結(jié)腸炎模型炎癥反應(yīng)，體重、結(jié)腸長(zhǎng)度和組織病理學(xué)都有所改善^[31]。下調(diào)STAT3的表達(dá)水平可改善咪喹莫特誘導(dǎo)的銀屑病皮膚病變^[42]。STAT5四聚體促進(jìn)腦膜中Th17細(xì)胞和單核細(xì)胞衍生細(xì)胞之間的相互作用，進(jìn)而參與實(shí)驗(yàn)性自身免疫性腦脊髓炎的發(fā)病機(jī)制^[43]。這些結(jié)果突出了STATs在自身免疫性疾病發(fā)病機(jī)制中的作用，可能為開(kāi)發(fā)新的治療方式提供幫助。

4. STATs與心血管疾病

STATs蛋白在心血管疾病中扮演著復(fù)雜且關(guān)鍵的角色。暴露于缺血/再灌注（I/R）損傷的心臟細(xì)胞經(jīng)歷細(xì)胞凋亡，并伴隨著STAT1的磷酸化、表達(dá)和轉(zhuǎn)錄活性的增加^[44]。STAT1過(guò)表達(dá)的細(xì)胞比STAT1缺乏的細(xì)胞更容易發(fā)生缺血誘導(dǎo)的細(xì)胞死亡。在暴露于I/R損傷下，與非轉(zhuǎn)基因同胎（NTG）相比，表達(dá)組成型活性STAT3（TG）小鼠心臟的梗死面積減少^[45]。TG心臟在I/R應(yīng)激反應(yīng)中產(chǎn)生的ROS程度低于NTG。與Apoe^-/-小鼠相比，高脂飲食（HFD）的STAT4缺乏Stat4^-/-Apoe^-/-小鼠，斑塊負(fù)擔(dān)減少，動(dòng)脈粥樣硬化顯著減輕^[46]。STAT5抑制劑治療通過(guò)減少炎癥顯著減輕了HFD誘導(dǎo)的Apoe^-/-小鼠的動(dòng)脈粥樣硬化^[47]。主動(dòng)脈弓縮窄（TAC）術(shù)后，小鼠心臟STAT6活性增加^[48]。與野生型小鼠相比，TAC術(shù)后STAT6^-/-小鼠舒張末期左心室內(nèi)徑顯著增加，并伴有收縮力受損，表明STAT6對(duì)心臟血流動(dòng)力學(xué)應(yīng)激起保護(hù)作用。這些結(jié)果提示STATs是心血管疾病中的“雙刃劍”，其在心肌保護(hù)、動(dòng)脈粥樣硬化、炎癥中的積極作用與負(fù)面效應(yīng)并存。

5. STATs與神經(jīng)退行性疾病

干擾素反應(yīng)和干擾素刺激基因（ISG）在神經(jīng)炎癥和神經(jīng)退行性疾病中發(fā)揮顯著作用。在阿爾茨海默病（AD）中的生物信息學(xué)分析顯示，Oas1g被鑒定為樞紐基因，與干擾素相關(guān)通路密切相關(guān)^[49]。siOas1g可以逆轉(zhuǎn)siSTAT1的作用，表明Oas1g可能通過(guò)STAT1途徑調(diào)節(jié)ISG。α-突觸核蛋白表達(dá)通過(guò)定位到細(xì)胞核、促進(jìn)STAT2激活、與神經(jīng)元中的磷酸化STAT2共定位以及促進(jìn)ISG的表達(dá)來(lái)支持神經(jīng)元特異性干擾素反應(yīng)^[50]。在幽門(mén)螺桿菌衍生的條件培養(yǎng)基（HPCM）處理的神經(jīng)元和神經(jīng)元-星形膠質(zhì)細(xì)胞共培養(yǎng)的細(xì)胞中發(fā)現(xiàn)STAT1、STAT3和AD相關(guān)蛋白APP和APOE4的表達(dá)升高^[51]。STAT3的特異性抑制降低了HPCM誘導(dǎo)的神經(jīng)元區(qū)室中pSTAT3和AD標(biāo)志物的表達(dá)。AD小鼠海馬體中IL-6-STAT3和cGAS-STING通路顯著激活，STAT3直接調(diào)控cGAS和STING基因的轉(zhuǎn)錄^[52]。IL-6缺乏通過(guò)調(diào)節(jié)STAT3-cGAS-STING通路來(lái)減輕AD小鼠的神經(jīng)炎癥。Aurantiamide（Aur）促進(jìn)小膠質(zhì)細(xì)胞的M2極化，提高AD小鼠的認(rèn)知能力，STAT6抑制劑處理可拮抗Aur的作用^[53]。這些數(shù)據(jù)提示STATs可能是調(diào)節(jié)神經(jīng)退行性疾病炎癥過(guò)程的潛在治療靶點(diǎn)。

圖4 幽門(mén)螺桿菌分泌物通過(guò)調(diào)節(jié)STAT3信號(hào)通路引發(fā)神經(jīng)炎癥和神經(jīng)變性

（圖片源于《Virulence》^[51]）

6. STATs與過(guò)敏性疾病

STATs信號(hào)通路整合多種關(guān)鍵細(xì)胞因子的信號(hào)，是過(guò)敏性疾病免疫病理機(jī)制的核心樞紐?？乖┞稌?huì)導(dǎo)致致敏小鼠肺部STAT6和STAT1激活^[54]。鼻內(nèi)抗T細(xì)胞免疫球蛋白和粘蛋白結(jié)構(gòu)域-1（TIM-1）給藥通過(guò)修復(fù)STAT1和STAT6通路來(lái)改善哮喘小鼠模型的過(guò)敏性肺部炎癥和重塑^[55]。Stat1^-/-小鼠經(jīng)曼氏血吸蟲(chóng)卵抗原（SEA）致敏后，鼻腔嗜酸性細(xì)胞受損，組胺誘導(dǎo)的鼻腔高反應(yīng)性明顯降低，提示STAT1參與了小鼠SEA誘導(dǎo)的過(guò)敏性鼻炎（AR）的發(fā)病機(jī)制^[56]。STAT3對(duì)于ILC2細(xì)胞功能至關(guān)重要，并促進(jìn)ILC2驅(qū)動(dòng)的肺部過(guò)敏性炎癥^[57]。STAT3缺乏或抑制STAT3線粒體易位顯著抑制ILC2過(guò)敏反應(yīng)并改善過(guò)敏性肺部炎癥。機(jī)制分析表明MicroRNA-146a通過(guò)積極靶向STAT5b增強(qiáng)AR中的調(diào)節(jié)性T細(xì)胞（Tregs）分化和功能^[58]。STAT6中雜合功能獲得變異引起的新的原發(fā)性特應(yīng)性疾病，導(dǎo)致嚴(yán)重的早發(fā)性過(guò)敏^[59]。深入了解STATs在特定過(guò)敏性疾病中的作用，不僅有助于闡明發(fā)病機(jī)制，也為開(kāi)發(fā)更精準(zhǔn)有效的靶向治療提供堅(jiān)實(shí)的理論基礎(chǔ)。

云克隆助力科學(xué)研究，為廣大科研人員提供相關(guān)檢測(cè)試劑產(chǎn)品，相關(guān)靶標(biāo)核心貨號(hào)如下：

更多科研試劑，歡迎訪問(wèn)云克隆官方網(wǎng)站：http://nceyjp.cn/

參考文獻(xiàn)

[1]Morris R, Kershaw NJ, Babon JJ. The molecular details of cytokine signaling via the JAK/STAT pathway. Protein Sci. 2018;27(12):1984-2009.

[2]Ribeiro D, Mel?o A, van Boxtel R, et al. STAT5 is essential for IL-7-mediated viability, growth, and proliferation of T-cell acute lymphoblastic leukemia cells. Blood Adv. 2018;2(17):2199-2213.

[3]Chan SR, Vermi W, Luo J, et al. STAT1-deficient mice spontaneously develop estrogen receptor α-positive luminal mammary carcinomas. Breast Cancer Res. 2012;14(1):R16.

[4]Li H, Zhang Y, Glass A, et al. Activation of signal transducer and activator of transcription-5 in prostate cancer predicts early recurrence. Clin Cancer Res. 2005;11(16):5863-5868.

[5]Cheng JM, Yao MR, Zhu Q, et al. Silencing of stat4 gene inhibits cell proliferation and invasion of colorectal cancer cells. J Biol Regul Homeost Agents. 2015;29(1):85-92.

[6]Wang C, Gao N, Yang L, et al. Stat4 rs7574865 polymorphism promotes the occurrence and progression of hepatocellular carcinoma via the Stat4/CYP2E1/FGL2 pathway. Cell Death Dis. 2022;13(2):130.

[7]Lee TK, Man K, Poon RT, et al. Signal transducers and activators of transcription 5b activation enhances hepatocellular carcinoma aggressiveness through induction of epithelial-mesenchymal transition. Cancer Res. 2006;66(20):9948-9956.

[8]Zhu H, Wang Z, Xu Q, et al. Inhibition of STAT1 sensitizes renal cell carcinoma cells to radiotherapy and chemotherapy. Cancer Biol Ther. 2012;13(6):401-407.

[9]Zeng T, Ye J, Wang H, Tian W. STAT2 act a prognostic biomarker and associated with immune infiltration in kidney renal clear cell carcinoma. Medicine (Baltimore). 2023;102(17):e33662.

[10]Benekli M, Xia Z, Donohue KA, et al. Constitutive activity of signal transducer and activator of transcription 3 protein in acute myeloid leukemia blasts is associated with short disease-free survival. Blood. 2002;99(1):252-257.

[11]Brady A, Gibson S, Rybicki L, et al. Expression of phosphorylated signal transducer and activator of transcription 5 is associated with an increased risk of death in acute myeloid leukemia. Eur J Haematol. 2012;89(4):288-293.

[12]Nakagawa T, Oda G, Kawachi H, Ishikawa T, Okamoto K, Uetake H. Nuclear Expression of p-STAT3 Is Associated with Poor Prognosis in ER(-) Breast Cancer. Clin Pract. 2022;12(2):157-167.

[13]Kusaba T, Nakayama T, Yamazumi K, et al. Activation of STAT3 is a marker of poor prognosis in human colorectal cancer. Oncol Rep. 2006;15(6):1445-1451.

[14]Wu WY, Li J, Wu ZS, Zhang CL, Meng XL. STAT3 activation in monocytes accelerates liver cancer progression. BMC Cancer. 2011;11:506.

[15]Chung SS, Aroh C, Vadgama JV. Constitutive activation of STAT3 signaling regulates hTERT and promotes stem cell-like traits in human breast cancer cells. PLoS One. 2013;8(12):e83971.

[16]Abdulghani J, Gu L, Dagvadorj A, et al. Stat3 promotes metastatic progression of prostate cancer. Am J Pathol. 2008;172(6):1717-1728.

[17]Cao H, Zhang J, Liu H, et al. IL-13/STAT6 signaling plays a critical role in the epithelial-mesenchymal transition of colorectal cancer cells. Oncotarget. 2016;7(38):61183-61198.

[18]Knitz MW, Darragh LB, Bickett TE, et al. Loss of cancer cell STAT1 improves response to radiation therapy and promotes T cell activation in head and neck squamous cell carcinoma. Cancer Immunol Immunother. 2022;71(5):1049-1061.

[19]Li Z, Chen C, Chen L, et al. STAT5a Confers Doxorubicin Resistance to Breast Cancer by Regulating ABCB1. Front Oncol. 2021;11:697950.

[20]Dechow A, Timonen S, Ianevski A, et al. Dual STAT3/STAT5 inhibition as a novel treatment strategy in T-prolymphocytic leukemia. Leukemia. 2025;39(6):1435-1448.

[21]Wang X, Hu R, Song Z, et al. Sorafenib combined with STAT3 knockdown triggers ER stress-induced HCC apoptosis and cGAS-STING-mediated anti-tumor immunity. Cancer Lett. 2022;547:215880.

[22]Zuo D, Shogren KL, Zang J, et al. Inhibition of STAT3 blocks protein synthesis and tumor metastasis in osteosarcoma cells. J Exp Clin Cancer Res. 2018;37(1):244.

[23]Subramaniam D, Angulo P, Ponnurangam S, et al. Suppressing STAT5 signaling affects osteosarcoma growth and stemness. Cell Death Dis. 2020;11(2):149.

[24]Kasperkovitz PV, Verbeet NL, Smeets TJ, et al. Activation of the STAT1 pathway in rheumatoid arthritis. Ann Rheum Dis. 2004;63(3):233-239.

[25]Liu J, Xue J, Xu B, et al. miR-135a-5p mediated down-regulation of STAT6 inhibits proliferation and induces apoptosis of fibroblast-like synoviocytes in rheumatoid arthritis. Am J Transl Res. 2022;14(5):3092-3103.

[26]Dong J, Wang QX, Zhou CY, Ma XF, Zhang YC. Activation of the STAT1 signalling pathway in lupus nephritis in MRL/lpr mice. Lupus. 2007;16(2):101-109.

[27]Harada T, Kyttaris V, Li Y, Juang YT, Wang Y, Tsokos GC. Increased expression of STAT3 in SLE T cells contributes to enhanced chemokine-mediated cell migration. Autoimmunity. 2007;40(1):1-8.

[28]Meshaal S, El Refai R, El Saie A, El Hawary R. Signal transducer and activator of transcription 5 is implicated in disease activity in adult and juvenile onset systemic lupus erythematosus. Clin Rheumatol. 2016;35(6):1515-1520.

[29]Schreiber S, Rosenstiel P, Hampe J, et al. Activation of signal transducer and activator of transcription (STAT) 1 in human chronic inflammatory bowel disease. Gut. 2002;51(3):379-385.

[30]Musso A, Dentelli P, Carlino A, et al. Signal transducers and activators of transcription 3 signaling pathway: an essential mediator of inflammatory bowel disease and other forms of intestinal inflammation. Inflamm Bowel Dis. 2005;11(2):91-98.

[31]Rosen MJ, Chaturvedi R, Washington MK, et al. STAT6 deficiency ameliorates severity of oxazolone colitis by decreasing expression of claudin-2 and Th2-inducing cytokines. J Immunol. 2013;190(4):1849-1858.

[32]Hald A, Andrés RM, Salskov-Iversen ML, Kjellerup RB, Iversen L, Johansen C. STAT1 expression and activation is increased in lesional psoriatic skin. Br J Dermatol. 2013;168(2):302-310.

[33]Johansen C, Rittig AH, Mose M, et al. STAT2 is involved in the pathogenesis of psoriasis by promoting CXCL11 and CCL5 production by keratinocytes. PLoS One. 2017;12(5):e0176994.

[34]Andrés RM, Hald A, Johansen C, Kragballe K, Iversen L. Studies of Jak/STAT3 expression and signalling in psoriasis identifies STAT3-Ser727 phosphorylation as a modulator of transcriptional activity. Exp Dermatol. 2013;22(5):323-328.

[35]Pertovaara M, Silvennoinen O, Isom?ki P. Cytokine-induced STAT1 activation is increased in patients with primary Sj?gren's syndrome. Clin Immunol. 2016;165:60-67.

[36]Pertovaara M, Silvennoinen O, Isom?ki P. STAT-5 is activated constitutively in T cells, B cells and monocytes from patients with primary Sj?gren's syndrome. Clin Exp Immunol. 2015;181(1):29-38.

[37]Namjou B, Sestak AL, Armstrong DL, et al. High-density genotyping of STAT4 reveals multiple haplotypic associations with systemic lupus erythematosus in different racial groups. Arthritis Rheum. 2009;60(4):1085-1095.

[38]Zervou MI, Goulielmos GN, Castro-Giner F, Tosca AD, Krueger-Krasagakis S. STAT4 gene polymorphism is associated with psoriasis in the genetically homogeneous population of Crete, Greece. Hum Immunol. 2009;70(9):738-741.

[39]Rueda B, Broen J, Simeon C, et al. The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype. Hum Mol Genet. 2009;18(11):2071-2077.

[40]Scheinman RI, Trivedi R, Vermillion S, Kompella UB. Functionalized STAT1 siRNA nanoparticles regress rheumatoid arthritis in a mouse model. Nanomedicine (Lond). 2011;6(10):1669-1682.

[41]Mori T, Miyamoto T, Yoshida H, et al. IL-1β and TNFα-initiated IL-6-STAT3 pathway is critical in mediating inflammatory cytokines and RANKL expression in inflammatory arthritis. Int Immunol. 2011;23(11):701-712.

[42]He Q, Wu X, Shi Q. Triptolide Inhibits Th17 Response by Upregulating microRNA-204-5p and Suppressing STAT3 Phosphorylation in Psoriasis. Genet Res (Camb). 2022;2022:7468396.

[43]Monaghan KL, Aesoph D, Ammer AG, et al. Tetramerization of STAT5 promotes autoimmune-mediated neuroinflammation. Proc Natl Acad Sci U S A. 2021;118(52):e2116256118.

[44]Stephanou A, Brar BK, Scarabelli TM, et al. Ischemia-induced STAT-1 expression and activation play a critical role in cardiomyocyte apoptosis. J Biol Chem. 2000;275(14):10002-10008.

[45]Oshima Y, Fujio Y, Nakanishi T, et al. STAT3 mediates cardioprotection against ischemia/reperfusion injury through metallothionein induction in the heart. Cardiovasc Res. 2005;65(2):428-435.

[46]Taghavie-Moghadam PL, Gjurich BN, Jabeen R, et al. STAT4 deficiency reduces the development of atherosclerosis in mice. Atherosclerosis. 2015;243(1):169-178.

[47]Wang X, Ding X, Yan J, et al. STAT5 inhibitor attenuates atherosclerosis via inhibition of inflammation: the role of STAT5 in atherosclerosis. Am J Transl Res. 2021;13(3):1422-1431.

[48]Hikoso S, Yamaguchi O, Higuchi Y, et al. Pressure overload induces cardiac dysfunction and dilation in signal transducer and activator of transcription 6-deficient mice. Circulation. 2004;110(17):2631-2637.

[49]Xie Z, Li L, Hou W, et al. Critical role of Oas1g and STAT1 pathways in neuroinflammation: insights for Alzheimer's disease therapeutics. J Transl Med. 2025;23(1):182.

[50]Monogue B, Chen Y, Sparks H, et al. Alpha-synuclein supports type 1 interferon signalling in neurons and brain tissue. Brain. 2022;145(10):3622-3636.

[51]Kandpal M, Baral B, Varshney N, et al. Gut-brain axis interplay via STAT3 pathway: Implications of Helicobacter pylori derived secretome on inflammation and Alzheimer's disease. Virulence. 2024;15(1):2303853.

[52]Liu M, Pan J, Li X, et al. Interleukin-6 deficiency reduces neuroinflammation by inhibiting the STAT3-cGAS-STING pathway in Alzheimer's disease mice. J Neuroinflammation. 2024;21(1):282.

[53]Shen H, He Z, Pei H, Zhai L, Guan Q, Wang G. Aurantiamide promotes M2 polarization of microglial cells to improve the cognitive ability of mice with Alzheimer's disease. Phytother Res. 2023;37(1):101-110.

[54]Chiba Y, Todoroki M, Misawa M. Antigen exposure causes activations of signal transducer and activator of transcription 6 (STAT6) and STAT1, but not STAT3, in lungs of sensitized mice. Immunopharmacol Immunotoxicol. 2011;33(1):43-48.

[55]Qiang L, Li Z, Wang G, et al. Anti-TIM1 suppresses airway inflammation and hyperresponsiveness via the STAT6 /STAT1 pathways in mice with allergic asthma. Pharmazie. 2022;77(1):14-20.

[56]Hattori H, Rosas LE, Okano M, Durbin JE, Nishizaki K, Satoskar AR. STAT1 is involved in the pathogenesis of murine allergic rhinitis. Am J Rhinol. 2007;21(2):241-247.

[57]Fu L, Zhao J, Huang J, et al. A mitochondrial STAT3-methionine metabolism axis promotes ILC2-driven allergic lung inflammation. J Allergy Clin Immunol. 2022;149(6):2091-2104.

[58]Zhang Y, Yang Y, Guo J, et al. miR-146a enhances regulatory T-cell differentiation and function in allergic rhinitis by targeting STAT5b. Allergy. 2022;77(2):550-558.

[59]Sharma M, Leung D, Momenilandi M, et al. Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease. J Exp Med. 2023;220(5):e20221755.