Ruscogenin Alleviates Myocardial Ischemia-Induced Ferroptosis through the Activation of BCAT1/BCAT2

Abstract

Ruscogenin (RUS), a natural steroidal sapogenin, exerts various biological activities. However, its effectiveness for preventing myocardial ischemia (MI) and its molecular mechanisms need further clarification. The model of MI mice and oxygen-glucose deprivation-induced cardiomyocytes injury was performed. RUS significantly alleviated MI, as evidenced by decreased infarct size, ameliorated biochemical indicators and cardiac pathological features, and markedly inhibited ferroptosis by means of the up-regulation of GPX4 and down-regulation of ACSL4 and FLC. Simultaneously, RUS notably mitigated cell injury and oxidative stress, and ameliorated ferroptosis in vitro. Subsequently, HPLC-Q-TOF/MS-based metabolomics identified BCAT1/BCAT2 as possible regulatory enzymes responsible for the cardioprotection of RUS. Importantly, RUS treatment significantly increased the expression of BCAT1 and BCAT2 in MI. Furthermore, we found that BCAT1 or BCAT2 siRNA significantly decreased cell viability, promoted ferroptosis, and increased Keap1 expression, and induced Nrf2 and HO-1 degradation in cardiomyocytes. Conversely, cardiac overexpression of BCAT1 or BCAT2 in MI mice activated the Keap1/Nrf2/HO-1 pathway. Moreover, RUS significantly activated the Keap1/Nrf2/HO-1 pathway in MI, whereas BCAT1 or BCAT2 siRNA partially weakened the protective effects of RUS, suggesting that RUS might suppress myocardial injury through BCAT1 and BCAT2. Overall, this study demonstrated that BCAT1/BCAT2 could alleviate MI-induced ferroptosis through the activation of the Keap1/Nrf2/HO-1 pathway and RUS exerted cardioprotective effects via BCAT1/BCAT2.

GSK-J4, a Specific Histone Lysine Demethylase 6A Inhibitor, Ameliorates Lipotoxicity to Cardiomyocytes via Preserving H3K27 Methylation and Reducing Ferroptosis

“…ACSL4 is a kind of fatty-acid-CoA ligases and is pro-ferroptosis by shaping cellular lipid composition ( 42 ). Interfering ACSL4 protein level either by pharmacological inhibitor ( 43 , 44 ) or by intrinsic active factors ( 45 ) is involved in ferroptosis in diabetic complications. Consistent with previous reports, we found significant ACSL4 elevation both in vivo and in vitro , and GSK-J4 could reverse its elevation.…”

Nature-Inspired Bioactive Compounds: A Promising Approach for Ferroptosis-Linked Human Diseases?

“…In pancreatic cancer cells, it increased intracellular ferrous ions as well as ROS production [ 190 ]. While in myocardial injury and acute kidney injury mice models, this compound has led to the upregulation of GPx4 expression, an increase in GSH concentration, and a decrease of intracellular iron and lipid peroxidation in a dose-dependent manner [ 191 , 192 ]. Curcumin from Curcuma longa has stimulated cell death by ferroptosis via accumulating iron ions in breast cancer cells and sabotaging GPx4 activity in glioblastoma cells [ 193 , 194 ].…”

Effects of Ferroptosis on Cardiovascular Diseases

“…Ruscogenin, a saponin derived from the root of the Chinese herb Ophiopogon japonicus , has a significant anti-inflammatory effect. It alleviates myocardial ischemia-induced ferroptosis by increasing the expression of BCAT1/BCAT2, activating the Keap1/Nrf2/HO-1 pathway, and upregulating GPX4 and downregulating ASCL4 expression [ 94 , 95 ]. Britanin is an antioxidant and anti-inflammatory active ingredient purified from Inula japonica Thunb, which can mediate the AMPK/GSK3 β /Nrf2 signaling pathway, increase the expression of GPX4, reduce ferroptosis, and improve myocardial I/R injury [ 96 ].…”