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Epidermal growth factor receptor (EGFR) signaling participates in adverse remodeling through activation of MAPK pathways, but the relationship between pharmacologically modulated EGFR turnover and cardiac remodeling remains insufficiently defined. Methods: This study investigated the protective effects of cycloastragenol (CAG), a triterpenoid sapogenin derived from Astragalus membranaceus, in Angiotensin II (Ang II)-induced cardiac remodeling and examined changes in EGFR turnover and associated MAPK signaling and autophagy-related processes. Circulating soluble EGFR was associated with heart failure severity after adjustment for age and sex. Separately, an independent exploratory transcriptomic analysis of left ventricular samples from GSE161472 showed that myocardial EGFR expression distinguished HFrEF from non-failing samples with an AUC of 0.870. Male C57BL\/6 mice subjected to continuous Ang II infusion at 500 ng\/kg\/min for 28 days were used to establish the in vivo cardiac remodeling model and evaluate the effects of CAG on cardiac function, myocardial injury, fibrosis, inflammation, oxidative stress, apoptosis, and autophagy-related changes, with enalapril used as a positive control. Primary cardiac fibroblasts were further used to assess proliferation, migration, collagen production, EGFR membrane accumulation, lysosomal trafficking, MAPK signaling, and autophagic flux. Circulating soluble EGFR increased with heart failure severity and was associated with BNP elevation, ventricular dilation, and reduced ejection fraction. Results: CAG improved cardiac performance, reduced myocardial injury markers, alleviated fibrosis and hypertrophy, and suppressed inflammatory and oxidative responses in Ang II-treated mice. In cardiac fibroblasts, CAG reduced sustained EGFR membrane accumulation, increased EGFR recovery in pan-ubiquitin immunoprecipitates and lysosomal localization, and accelerated EGFR protein turnover, consistent with a predominantly lysosome-associated pathway. The K716R mutation attenuated CAG-associated changes in EGFR turnover, MAPK phosphorylation, and autophagic flux. Conclusions: These findings suggest that CAG attenuates Ang II-induced cardiac remodeling and is associated with enhanced EGFR lysosomal turnover, accompanied by changes in MAPK signaling and autophagy-related processes.<\/jats:p>","DOI":"10.3390\/ph19091360","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T16:47:13Z","timestamp":1787849233000},"page":"1360","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cycloastragenol Attenuates Angiotensin II-Induced Cardiac Remodeling in Association with Enhanced EGFR Lysosomal Turnover and Changes in MAPK Signaling and Autophagy"],"prefix":"10.3390","volume":"19","author":[{"given":"Dongsheng","family":"Wei","sequence":"first","affiliation":[{"name":"School of Life Sciences, Beijing University of Chinese Medicine, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang 110847, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Beijing University of Chinese Medicine, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Beijing University of Chinese Medicine, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongyue","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Beijing University of Chinese Medicine, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menglan","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Beijing University of Chinese Medicine, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiming","family":"Cao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine, Shenyang 110847, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqing","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Beijing University of Chinese Medicine, Beijing 100029, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e11","DOI":"10.15420\/cfr.2023.05","article-title":"Global public health burden of heart failure: An updated review","volume":"9","author":"Shahim","year":"2023","journal-title":"Card. 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