Pharmacol Res Perspect. 2026 Dec;14(6):e70334. doi: 10.1002/prp2.70334.
ABSTRACT
Pathological cardiac hypertrophy is initially an adaptive response to sustained mechanical, neurohormonal, or metabolic stress; however, it can progress to fibrosis, contractile dysfunction, arrhythmia, and heart failure. Ferroptosis is a type of regulated cell death caused by iron-dependent phospholipid peroxidation. Evidence consistent with ferroptosis, such as disrupted iron homeostasis, lipid peroxidation, mitochondrial dysfunction and impaired antioxidant defense, has been reported in experimental models of pathological cardiac hypertrophy; however, these findings do not by themselves establish ferroptosis as a cause of hypertrophic remodeling. Astragaloside IV (AS-IV) is a cycloartane-type triterpene saponin from Astragalus species that has shown anti-hypertrophic, antioxidant, anti-inflammatory, metabolic-regulatory and mitochondrial-protective effects in experimental cardiovascular models. AS-IV has also shown anti-ferroptotic effects in several cardiac and extra-cardiac disease models by means of Nrf2-centred antioxidant defense, regulation of SLC7A11/GPX4, p53 signaling, CD36-dependent lipid handling, and 14-3-3η-linked regulation of GPX4 stability. Nevertheless, whether ferroptosis inhibition directly contributes to the anti-hypertrophic effect of AS-IV in pathological cardiac hypertrophy remains unproven because direct causal validation in dedicated hypertrophy models is lacking. This review collects evidence on the biology of ferroptosis in pathological cardiac hypertrophy, the established anti-hypertrophic pharmacology of AS-IV, its reported anti-ferroptotic effects, and relevant pharmacokinetic considerations. Based on this, we propose that AS-IV may reduce the susceptibility of cardiomyocytes to ferroptosis and thus partially inhibit pathological cardiac remodeling; however, this is not yet a proven mechanism. Direct verification requires etiologically distinct hypertrophy models, multi-modal ferroptosis measurements, targeted genetic or pharmacological disruption, dose-response and pharmacokinetic experiments, and cell-type-resolved analysis.
PMID:42888503 | DOI:10.1002/prp2.70334