British journal of pharmacology · 2026
Targeting ferroptosis with chenodeoxycholic acid improves residual cardiac dysfunction after surgical ventricular reconstruction.
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Wang Qiuhan, Chen Lu, Shen Bingxiang, Yan Junyu, Fu Xiaokang, Cheng Ao, Han Dan, Bin Jianping, Liao Yulin, Ma Siyuan
Аннотация
BACKGROUND AND PURPOSE: Surgical ventricular reconstruction (SVR) partially reverses left ventricular remodelling in postinfarction heart failure, yet residual cardiac dysfunction persists through unknown mechanisms. We investigated ferroptosis involvement in post-SVR pathology and explored pharmacological interventions.
EXPERIMENTAL APPROACH: Myocardial infarction (MI) was induced in C57BL/6 mice followed by SVR at 4 weeks. Cardiac function was assessed by echocardiography and pressure-volume catheterization. Ferroptosis biomarkers were quantified. Connectivity Map analysis identified candidate compounds validated in Erastin-challenged AC16 cardiomyocytes and SVR mouse models.
KEY RESULTS: Compared with MI group, SVR improved the left ventricular end-diastolic volume index by 36.8% but showed persistent iron overload, glutathione depletion and elevated malondialdehyde. Transcriptomic analysis identified 90 ferroptosis-related differentially expressed genes following SVR. Connectivity Map prioritized three ferroptosis inhibitors, and chenodeoxycholic acid (CDCA) exhibited superior efficacy. Farnesoid X receptor (FXR) knockdown in AC16 cardiomyocytes exacerbated erastin-induced ferroptosis, while CDCA co-treatment significantly reduced erastin-induced ROS production, upregulated glutathione peroxidase 4 (GPX4) expression, and restored superoxide dismutase activity, rescued the ferroptotic phenotype and reversed associated molecular changes in FXR-knockdown cells. In SVR-treated mice, 3-week CDCA administration (50 mg·kg-1·day-1) reduced myocardial iron deposition by 14.8%, improved left ventricular ejection fraction from 23.73% to 31.61% and restored GSH/GSSG ratio from 1.645 to 1.988. CDCA up-regulated GPX4 expression by 1.573-fold compared with the vehicle group.
CONCLUSION AND IMPLICATIONS: SVR paradoxically exacerbates ferroptosis in residual myocardium through iron dysregulation and antioxidant depletion. CDCA, a primary bile acid activating FXR signalling, is a novel pharmacological strategy to mitigate post-SVR ferroptosis and improve cardiac outcomes.
EXPERIMENTAL APPROACH: Myocardial infarction (MI) was induced in C57BL/6 mice followed by SVR at 4 weeks. Cardiac function was assessed by echocardiography and pressure-volume catheterization. Ferroptosis biomarkers were quantified. Connectivity Map analysis identified candidate compounds validated in Erastin-challenged AC16 cardiomyocytes and SVR mouse models.
KEY RESULTS: Compared with MI group, SVR improved the left ventricular end-diastolic volume index by 36.8% but showed persistent iron overload, glutathione depletion and elevated malondialdehyde. Transcriptomic analysis identified 90 ferroptosis-related differentially expressed genes following SVR. Connectivity Map prioritized three ferroptosis inhibitors, and chenodeoxycholic acid (CDCA) exhibited superior efficacy. Farnesoid X receptor (FXR) knockdown in AC16 cardiomyocytes exacerbated erastin-induced ferroptosis, while CDCA co-treatment significantly reduced erastin-induced ROS production, upregulated glutathione peroxidase 4 (GPX4) expression, and restored superoxide dismutase activity, rescued the ferroptotic phenotype and reversed associated molecular changes in FXR-knockdown cells. In SVR-treated mice, 3-week CDCA administration (50 mg·kg-1·day-1) reduced myocardial iron deposition by 14.8%, improved left ventricular ejection fraction from 23.73% to 31.61% and restored GSH/GSSG ratio from 1.645 to 1.988. CDCA up-regulated GPX4 expression by 1.573-fold compared with the vehicle group.
CONCLUSION AND IMPLICATIONS: SVR paradoxically exacerbates ferroptosis in residual myocardium through iron dysregulation and antioxidant depletion. CDCA, a primary bile acid activating FXR signalling, is a novel pharmacological strategy to mitigate post-SVR ferroptosis and improve cardiac outcomes.