Therapeutic Modulation of Mitophagy by Cafestol in Pressure Overload–Induced Cardiac Hypertrophy and Fibrosis

Background/Objectives: Mitophagy, the selective clearance of damaged mitochondria, is critical in regulating cardiac hypertrophy and fibrosis under pressure overload. Targeting mitophagy offers a potential therapeutic avenue for mitigating adverse cardiac remodeling. This study examined the cardioprotective effects of cafestol—a coffee-derived diterpene—on pressure overload-induced cardiac hypertrophy and fibrosis, with a focus 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. Cardiac function was assessed through echocardiography; histological and molecular analyses quantified fibrosis, inflammation, and apoptosis. CD68, CTGF, DDR2, α-SMA, CD44, galectin-3, collagen I, GAPDH, Bcl-2, Bax, cleaved caspase-3, GRP78, p-ERK/ERK, ATF4, p-mTOR/mTOR, and p62 expression was evaluated. Transmission electron microscopy (TEM) was used to visualize autophagosomes and assess mitochondrial morphology. Results: TAC induced marked cardiac hypertrophy and fibrosis, with increased expression of fibrotic (CTGF, DDR2, α-SMA, collagen I), inflammatory (CD68, CD44, galectin-3), and apoptotic markers (Bax, cleaved caspase-3) and, endoplasmic reticulum stress indicators (GRP78, ATF4). TEM revealed increased autophagosome formation and disrupted mitochondrial architecture in TAC hearts. Cafestol significantly reduced collagen deposition, immune cell infiltration, and apoptotic signaling; enhanced Bcl-2 expression; and restored p62. TEM demonstrated decreased autophagosome accumulation and preserved mitochondrial structure in cafestol-treated mice, consistent with improved mitophagic flux and mitochondrial homeostasis. Conclusions: Cafestol attenuates pressure overload-induced cardiac remodeling by modulating mitophagy, suppressing fibrotic and inflammatory responses, and preserving mitochondrial integrity. TEM findings confirm its role in restoring autophagic balance, underscoring its therapeutic potential in cardiovascular disease.