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However, the role of 4-HCH in the regulation of cardiac remodeling remains uncertain. A cardiac remodeling model was established in male C57BL\/6\u2009J mice via subcutaneous Ang II (1000 or 300\u2009ng\/kg\/min) for 2 weeks. Mice were treated with 4-HCH (20 or 40\u2009mg\/kg\/day) or vehicle control. Systolic blood pressure (SBP) was measured using a tail-cuff method, and echocardiography assessed cardiac function. Histopathological staining evaluated cardiomyocyte hypertrophy, fibrosis, inflammation, and superoxide production. Network pharmacology analysis identified potential core targets and pathways mediating the effects of 4-HCH. Expression of inflammatory cytokines and proteins related to hypertrophy, fibrosis, inflammation, and oxidative stress was assessed by quantitative real-time PCR (qPCR) and Western blotting. Our results indicated that 4-HCH significantly ameliorated Ang II-induced hypertension, cardiomyocyte hypertrophy, fibroblast activation, fibrosis, inflammation, superoxide production, and cardiac function. Network pharmacology analysis identified the PI3K-AKT pathway as a crucial mechanism underlying the effects of 4-HCH, with experimental verification demonstrating that it inhibits cardiac remodeling by downregulating this pathway and its downstream effectors, including mTOR\/ERK, TGF-\u03b2\/Smad2\/3, NF-\u03baB, and NOX1 independent of its blood pressure-lowering effects. These results reveal for the first time that 4-HCH alleviates cardiac remodeling, emphasizing its potential as a therapeutic agent for HF.<\/jats:p>","DOI":"10.1038\/s41440-024-02068-w","type":"journal-article","created":{"date-parts":[[2024,12,24]],"date-time":"2024-12-24T01:49:42Z","timestamp":1735004982000},"page":"1054-1067","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["4-Hydroxychalcone attenuates AngII-induced cardiac remodeling and dysfunction via regulating PI3K\/AKT pathway"],"prefix":"10.1038","volume":"48","author":[{"given":"Xiao","family":"Han","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian-Qiu","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Kang","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing-Hua","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng-Xing","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Long","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,24]]},"reference":[{"key":"2068_CR1","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1038\/nrcardio.2011.154","volume":"8","author":"O Gjesdal","year":"2011","unstructured":"Gjesdal O, Bluemke DA, Lima JA. 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