{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:37:18Z","timestamp":1787027838412,"version":"build-2736575974"},"reference-count":41,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T00:00:00Z","timestamp":1763942400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005046","name":"Natural Science Foundation of Heilongjiang Province","doi-asserted-by":"publisher","award":["LH2022C041"],"award-info":[{"award-number":["LH2022C041"]}],"id":[{"id":"10.13039\/501100005046","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2024M750390"],"award-info":[{"award-number":["2024M750390"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Young Talents\u2019 Project of Northeast Agricultural University","award":["23YJQA02"],"award-info":[{"award-number":["23YJQA02"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Chronic stress adversely affects and compromises physiological well-being in humans, inducing hepatic injury, with its pathogenesis mechanistically linked to alterations in macrophage polarization and the regulation of the inflammatory microenvironment. Chlorogenic acid (CGA), a principal active component of Lonicera japonica (honeysuckle), has been shown to have therapeutic effects on various liver diseases. However, the specific mechanism by which CGA confers hepatoprotective effects through the modulation of macrophage polarization and inflammatory responses remains unclear. In this study, rats were subjected to 6 h of daily restraint stress for 21 consecutive days, with the experimental group receiving concurrent administration of CGA (100 mg\/kg, via gavage). The results demonstrated that CGA intervention effectively mitigated chronic stress-induced impairments in growth performance and hepatic structural and functional integrity. CGA significantly inhibited M1 macrophage polarization and the expression of pro-inflammatory cytokines (IL-6, IL-1\u03b2, and TNF-\u03b1), while simultaneously promoting M2 polarization and the expression of the anti-inflammatory cytokine IL-10. Furthermore, the administration of CGA was found to inhibit the activation of the JAK2\/STAT3 signaling pathway. Additionally, the use of the JAK2\/STAT3 signaling pathway inhibitor, S3I-201, demonstrated effects similar to those observed with CGA treatment. In summary, CGA modulates macrophage polarization and the inflammatory response through the regulation of the JAK2\/STAT3 signaling pathway, thereby mitigating the liver injury induced by chronic stress.<\/jats:p>","DOI":"10.3390\/cells14231848","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T10:24:17Z","timestamp":1763979857000},"page":"1848","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Targeting JAK2\/STAT3-Dependent Macrophage Polarization by Chlorogenic Acid Attenuates Hepatic Inflammation in Chronic Stress"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6095-9860","authenticated-orcid":false,"given":"Yaxin","family":"Ji","sequence":"first","affiliation":[{"name":"Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyang","family":"Tan","sequence":"additional","affiliation":[{"name":"Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Cheng","sequence":"additional","affiliation":[{"name":"Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqing","family":"Yu","sequence":"additional","affiliation":[{"name":"Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahuan","family":"Hu","sequence":"additional","affiliation":[{"name":"Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxing","family":"Wang","sequence":"additional","affiliation":[{"name":"Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haotian","family":"Yang","sequence":"additional","affiliation":[{"name":"Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"},{"name":"Heilongjiang Academy of Agricultural Science Branch of Animal Husbandry and Veterinary Branch, Qiqihar 161000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guofeng","family":"Feng","sequence":"additional","affiliation":[{"name":"Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjing","family":"Jiao","sequence":"additional","affiliation":[{"name":"Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7671-6908","authenticated-orcid":false,"given":"Honggang","family":"Fan","sequence":"additional","affiliation":[{"name":"Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Knezevic, E., Nenic, K., Milanovic, V., and Knezevic, N.N. (2023). The Role of Cortisol in Chronic Stress, Neurodegenerative Diseases, and Psychological Disorders. Cells, 12.","DOI":"10.3390\/cells12232726"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.bbi.2025.02.015","article-title":"Targeting TNIP1 as a new therapeutic avenue for major depressive disorder","volume":"126","author":"Hung","year":"2025","journal-title":"Brain, Behav. Immun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2823","DOI":"10.1016\/j.cell.2023.05.001","article-title":"The enteric nervous system relays psychological stress to intestinal inflammation","volume":"186","author":"Schneider","year":"2023","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Shea, S., Lionis, C., Kite, C., Atkinson, L., Chaggar, S.S., Randeva, H.S., and Kyrou, I. (2021). Non-Alcoholic Fatty Liver Disease (NAFLD) and Potential Links to Depression, Anxiety, and Chronic Stress. Biomedicines, 9.","DOI":"10.3390\/biomedicines9111697"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Xu, M.-Y., Guo, C.-C., Li, M.-Y., Lou, Y.-H., Chen, Z.-R., Liu, B.-W., and Lan, L. (2022). Brain-gut-liver axis: Chronic psychological stress promotes liver injury and fibrosis via gut in rats. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.1040749"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Li, C., Chen, Y., Yuan, X., He, L., Li, X., Huang, S., Hou, S., and Liang, J. (2020). Vitexin ameliorates chronic stress plub high fat diet-induced nonalcoholic fatty liver disease by inhibiting inflammation. Eur. J. Pharmacol., 882.","DOI":"10.1016\/j.ejphar.2020.173264"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.amjsurg.2019.07.006","article-title":"Chronic stress induces persistent low-grade inflammation","volume":"218","author":"Miller","year":"2019","journal-title":"Am. J. Surg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/j.jhep.2021.11.008","article-title":"Gut-derived systemic inflammation as a driver of depression in chronic liver disease","volume":"76","author":"Kronsten","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2310","DOI":"10.1016\/j.immuni.2024.08.016","article-title":"Notch signaling regulates macrophage-mediated inflammation in metabolic dysfunction-associated steatotic liver disease","volume":"57","author":"Guo","year":"2024","journal-title":"Immunity"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Bhat, A., Chaudhary, S., Yadav, G., Parasar, A., Bihari, C., Maras, J., and Sarin, S.K. (2020). Aspirin induces autophagy and alleviates liver fibrosis by reducing oxidative stress and inflammation in mice model of chronic liver injury. J. Hepatol., 73.","DOI":"10.1016\/S0168-8278(20)31532-4"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12967-024-05219-2","article-title":"FGF4 ameliorates the liver inflammation by reducing M1 macrophage polarization in experimental autoimmune hepatitis","volume":"22","author":"Lin","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Qian, Z., Xiong, W., Mao, X., and Li, J. (2024). Macrophage Perspectives in Liver Diseases: Programmed Death, Related Biomarkers, and Targeted Therapy. Biomolecules, 14.","DOI":"10.3390\/biom14060700"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"10932","DOI":"10.1021\/acs.jafc.3c02787","article-title":"The Therapeutic Potential of Hydroxycinnamic Acid Derivatives in Parkinson\u2019s Disease: Focus on In Vivo Research Advancements","volume":"71","author":"Yang","year":"2023","journal-title":"J. Agric. Food Chem."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Qian, F., Zhu, Z., Luo, C., Qi, R., Wei, L., Bo, L., Jiang, W., and Mao, C. (2025). Chlorogenic Acid Ameliorates Chronic Unpredictable Stress-Induced Diminished Ovarian Reserve Through Ovarian Renin-Angiotensin System. Mol. Nutr. Food Res., 69.","DOI":"10.1002\/mnfr.202400814"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Shi, H., Shi, A., Dong, L., Dai, F., Lu, X., and Wang, Y. (2016). Sa1557 Chlorogenic Acid Facilitates NRF2-Mediated Antioxidant Gene and Protects Against CCL4-Induced Liver Injury. Gastroenterology, 150.","DOI":"10.1016\/S0016-5085(16)33600-9"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2685","DOI":"10.1007\/s10565-023-09795-9","article-title":"EGR1 is crucial for the chlorogenic acid\u2013provided promotion on liver regeneration and repair after APAP-induced liver injury","volume":"39","author":"Wei","year":"2023","journal-title":"Cell Biol. Toxicol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Song, R., Yu, S., Peng, W., Tang, J., and Chen, M. (2024). SAT-395 ROS-dependent activation of JAK2\/STAT3 pathway contributes to HBV-induced liver inflammation. J. Hepatol., 80.","DOI":"10.1016\/S0168-8278(24)02097-X"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.molimm.2024.01.012","article-title":"IFITM3 mediates inflammation induced myocardial injury through JAK2\/STAT3 signaling pathway","volume":"167","author":"Xiong","year":"2024","journal-title":"Mol. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4078","DOI":"10.7150\/thno.52574","article-title":"Electroacupuncture ameliorates intestinal inflammation by activating \u03b17nAChR-mediated JAK2\/STAT3 signaling pathway in postoperative ileus","volume":"11","author":"Yang","year":"2021","journal-title":"Theranostics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"793","DOI":"10.4062\/biomolther.2024.033","article-title":"Jolkinolide B Ameliorates Liver Inflammation and Lipogenesis by Regulating JAK\/STAT3 Pathway","volume":"32","author":"Noh","year":"2024","journal-title":"Biomol. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.freeradbiomed.2022.12.085","article-title":"Exosomal RBP4 potentiated hepatic lipid accumulation and inflammation in high-fat-diet-fed mice by promoting M1 polarization of Kupffer cells","volume":"195","author":"Yao","year":"2022","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"\u0110iki\u0107, D., Bogdanovi\u0107, A., Markovi\u0107, D., Mitrovi\u0107-Ajti\u0107, O., Suboti\u010dki, T., Dikli\u0107, M., Vukoti\u0107, M., Dragojevi\u0107, T., \u017divkovi\u0107, E., and Santibanez, J.F. (2022). Inflammation Promotes Oxidative and Nitrosative Stress in Chronic Myelogenous Leukemia. Biomolecules, 12.","DOI":"10.3390\/biom12020247"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Tang, Q., Xing, C., Li, M., Jia, Q., Bo, C., and Zhang, Z. (2022). Pirfenidone ameliorates pulmonary inflammation and fibrosis in a rat silicosis model by inhibiting macrophage polarization and JAK2\/STAT3 signaling pathways. Ecotoxicol. Environ. Saf., 244.","DOI":"10.1016\/j.ecoenv.2022.114066"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Yang, X.-Y., Jiang, D., Wang, Y.-Z., Duan, M.-Y., Huang, Y.-W., Wang, X.-J., Xiang, Z.-M., Sheng, J., and Zhu, Q.-Q. (2024). Chlorogenic acid alleviates renal fibrosis by reducing lipid accumulation in diabetic kidney disease through suppressing the Notch1 and Stat3 signaling pathway. Ren. Fail., 46.","DOI":"10.1080\/0886022X.2024.2371988"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Li, Q.-Q., Yan, J.-H., Zhou, Z.-E., Geng, X., and Xiong, J.-H. (2024). Enhanced anti-inflammatory activity of chlorogenic acid via folic acid-TPGS-modified liposomes encapsulation: Characterization and In vivo evaluation on colitis mice. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1437773"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10532","DOI":"10.1021\/acs.jafc.2c04593","article-title":"Effect of Chlorogenic Acid via Upregulating Resolvin D1 Inhibiting the NF-\u03baB Pathway on Chronic Restraint Stress-Induced Liver Inflammation","volume":"70","author":"Wang","year":"2022","journal-title":"J. Agric. Food Chem."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Zhao, S., Yang, T., Hou, X., Zhang, H., Zhao, Y., Wang, H., Sun, N., Tan, H., Zhang, J., and Fan, H. (2022). Chlorogenic acid ameliorates chronic stress-induced prefrontal cortex injury through activating the 5-HT\/BDNF signaling pathway in rats. Food Biosci., 50.","DOI":"10.1016\/j.fbio.2022.102179"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.biopha.2016.11.063","article-title":"Anticancer effects of novel thalidomide analogs in A549 cells through inhibition of vascular endothelial growth factor and matrix metalloproteinase-2","volume":"85","author":"Kasai","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Chen, Z., Yang, Y., Mi, S., Fan, Q., Sun, X., Deng, B., Wu, G., Li, Y., Zhou, Q., and Ruan, Z. (2019). Hepatoprotective effect of chlorogenic acid against chronic liver injury in inflammatory rats. J. Funct. Foods, 62.","DOI":"10.1016\/j.jff.2019.103540"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4353","DOI":"10.1021\/acs.jafc.2c01196","article-title":"Chlorogenic Acid Alleviates Chronic Stress-Induced Duodenal Ferroptosis via the Inhibition of the IL-6\/JAK2\/STAT3 Signaling Pathway in Rats","volume":"70","author":"Zhao","year":"2022","journal-title":"J. Agric. Food Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9381","DOI":"10.1021\/acs.jafc.3c00953","article-title":"Chlorogenic Acid Alleviates Chronic Stress-Induced Intestinal Damage by Inhibiting the P38MAPK\/NF-\u03baB Pathway","volume":"71","author":"Zhao","year":"2023","journal-title":"J. Agric. Food Chem."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Wang, H., Wang, X., Wang, H., Shao, S., and Zhu, J. (2024). Chronic Corticosterone Administration-Induced Mood Disorders in Laboratory Rodents: Features, Mechanisms, and Research Perspectives. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252011245"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Guo, B., Yan, L., Tang, Y., Du, J., Dai, Z., Liu, J., Lei, M., Hou, Z., and Zhu, H. (2024). Green Light Mitigates Cyclic Chronic Heat-Stress-Induced Liver Oxidative Stress and Inflammation via NF-\u03baB Pathway Inhibition in Geese. Antioxidants, 13.","DOI":"10.3390\/antiox13070772"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Li, D., Tong, Q., Shi, Z., Zheng, W., Wang, Y., Li, B., and Yan, G. (2020). Effects of Cold Stress and Ammonia Concentration on Productive Performance and Egg Quality Traits of Laying Hens. Animals, 10.","DOI":"10.3390\/ani10122252"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Kandilarov, I., Gardjeva, P., Georgieva-Kotetarova, M., Zlatanova, H., Vilmosh, N., Kostadinova, I., Katsarova, M., Atliev, K., and Dimitrova, S. (2023). Effect of Plant Extracts Combinations on TNF-\u03b1, IL-6 and IL-10 Levels in Serum of Rats Exposed to Acute and Chronic Stress. Plants, 12.","DOI":"10.3390\/plants12173049"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.jhep.2024.06.016","article-title":"Inflammasomes in chronic liver disease: Hepatic injury, fibrosis progression and systemic inflammation","volume":"81","author":"Taru","year":"2024","journal-title":"J. Hepatol."},{"key":"ref_37","first-page":"478","article-title":"Chlorogenic acid attenuates liver apoptosis and inflammation in endoplasmic reticulum stress-induced mice","volume":"26","author":"Moslehi","year":"2023","journal-title":"Iran. J. Basic Med. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Mirsanei, Z., Heidari, N., Hazrati, A., Asemani, Y., Niknam, B., Yousefi, Z., and Jafari, R. (2023). Oleuropein reduces LPS-induced inflammation via stimulating M2 macrophage polarization. Biomed. Pharmacother., 163.","DOI":"10.1016\/j.biopha.2023.114857"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Xiong, S., Su, X., Kang, Y., Si, J., Wang, L., Li, X., and Ma, K. (2023). Effect and mechanism of chlorogenic acid on cognitive dysfunction in mice by lipopolysaccharide-induced neuroinflammation. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1178188"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1002\/kjm2.12585","article-title":"Paeonol alleviates placental inflammation and apoptosis in preeclampsia by inhibiting the JAK2\/STAT3 signaling pathway","volume":"38","author":"Wang","year":"2022","journal-title":"Kaohsiung J. Med. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Yao, J., and Zhao, Y. (2023). Lp-PLA2 silencing ameliorates inflammation and autophagy in nonalcoholic steatohepatitis through inhibiting the JAK2\/STAT3 pathway. PeerJ, 11.","DOI":"10.7717\/peerj.15639"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/23\/1848\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T05:23:33Z","timestamp":1764134613000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/23\/1848"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,24]]},"references-count":41,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["cells14231848"],"URL":"https:\/\/doi.org\/10.3390\/cells14231848","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,24]]}}}