{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T11:07:58Z","timestamp":1764068878273,"version":"3.45.0"},"reference-count":29,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council (NSTC), Taiwan","award":["NSTC 112-2314-B-038-105","MOST 111-2314-B-039-014"],"award-info":[{"award-number":["NSTC 112-2314-B-038-105","MOST 111-2314-B-039-014"]}]},{"DOI":"10.13039\/501100007300","name":"China Medical University, Taiwan","doi-asserted-by":"publisher","award":["CMU111-MF-102"],"award-info":[{"award-number":["CMU111-MF-102"]}],"id":[{"id":"10.13039\/501100007300","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Mitophagy, the selective removal of damaged mitochondria, plays a pivotal role in regulating cardiac hypertrophy and fibrosis under pressure overload. Targeting mitophagy may help mitigate adverse cardiac remodeling. This preclinical study examined the effects of cafestol, a coffee-derived diterpene, on pressure overload-induced cardiac hypertrophy and fibrosis in mice, with emphasis on mitophagy modulation and mitochondrial ultrastructure. Methods: Male normotensive mice underwent transverse aortic constriction (TAC) and received cafestol at 2, 10, or 50 mg\/kg\/day via oral gavage for 28 days. Cardiac function was assessed by echocardiography. Histological and molecular analyses quantified fibrosis, inflammation, and apoptosis. Protein expression of CD68, CTGF, DDR2, \u03b1-SMA, CD44, galectin-3 (Gal3), collagen I, GAPDH, Bcl-2, Bax, cleaved caspase-3, GRP78, p-ERK\/ERK, ATF4, p-mTOR\/mTOR, and p62 was evaluated. Transmission electron microscopy (TEM) was used to assess autophagosome formation and mitochondrial morphology. Results: TAC induced significant cardiac hypertrophy and fibrosis, accompanied by elevated expression of fibrotic (CTGF, DDR2, \u03b1-SMA, collagen I), inflammatory (CD68, CD44, Gal3), apoptotic (Bax, cleaved caspase-3), and endoplasmic reticulum stress markers (GRP78, ATF4). TEM revealed increased autophagosome accumulation and disrupted mitochondrial architecture. Cafestol treatment reduced collagen deposition, immune cell infiltration, and apoptotic signaling; enhanced Bcl-2 expression; and restored p62 levels. TEM findings demonstrated decreased autophagosome burden and preserved mitochondrial structure, consistent with improved mitophagic flux and mitochondrial homeostasis. Conclusions: Cafestol mitigated pressure overload-induced cardiac remodeling in mice by modulating mitophagy, suppressing fibrotic and inflammatory responses, and preserving mitochondrial integrity. These findings support further investigation of cafestol\u2019s mechanisms and safety profile in preclinical models of cardiovascular disease.<\/jats:p>","DOI":"10.3390\/nu17233680","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T10:46:18Z","timestamp":1764067578000},"page":"3680","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Therapeutic Modulation of Mitophagy by Cafestol in Pressure Overload-Induced Cardiac Hypertrophy and Fibrosis"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6067-1306","authenticated-orcid":false,"given":"Wen-Rui","family":"Hao","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Ministry of Health and Welfare, Taipei Medical University, New Taipei City 23561, Taiwan"},{"name":"Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11002, Taiwan"},{"name":"Taipei Heart Institute, Taipei Medical University, Taipei 11002, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4888-3709","authenticated-orcid":false,"given":"Chun-Chao","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Ministry of Health and Welfare, Taipei Medical University, New Taipei City 23561, Taiwan"},{"name":"Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11002, Taiwan"},{"name":"Taipei Heart Institute, Taipei Medical University, Taipei 11002, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guan-Ci","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Department of Internal Medicine, Shuang Ho Hospital, Ministry of Health and Welfare, Taipei Medical University, New Taipei City 23561, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia-Hong","family":"Lin","sequence":"additional","affiliation":[{"name":"Taipei Municipal Chenggong High School, Taipei City 100025, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huan-Yuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Academia Sinica, Taipei City 115201, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ju-Chi","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Ministry of Health and Welfare, Taipei Medical University, New Taipei City 23561, Taiwan"},{"name":"Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11002, Taiwan"},{"name":"Taipei Heart Institute, Taipei Medical University, Taipei 11002, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9155-4169","authenticated-orcid":false,"given":"Tzu-Hurng","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine, College of Medicine, China Medical University, Taichung 404328, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin-Jer","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Academia Sinica, Taipei City 115201, Taiwan"},{"name":"Division of Cardiology, Department of Internal Medicine and Graduate Institute of Clinical Medical Science, China Medical University, Taichung City 404328, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1055\/a-1793-6134","article-title":"Cardiac Remodeling in Hypertension: Clinical Impact on Brain, Heart, and Kidney Function","volume":"54","author":"Mavrogeni","year":"2022","journal-title":"Horm. 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