Aug 2026· International Journal of Biochemistry and Cell Biology· pp.
107014
· 0 citations· 40 references
Medicine
TL;DR
Results showed that FMN improved lean mass, grip strength, mitochondrial membrane potential, and ATP production, while reducing ROS and ferroptosis by regulating ACSL4, GPX4, and SLC7A11.
Abstract
Age-related muscle atrophy is closely associated with mitochondrial dysfunction and ferroptosis. This study established a D-gal-induced sarcopenia model in aged mice and a C2C12/GM17940 cell myotube senescence model, with young/control, old/D-gal, and formononetin (FMN) intervention groups. After shSIRT1 transfection and mitochondrial-targeted antioxidant Mito-C intervention, the effects and mechanism of FMN were detected by measuring mouse phenotypic indicators (lean mass, hindlimb muscle mass, grip strength) and cell indicators (viability, mitochondrial membrane potential, ROS, ATP, ferroptosis-related proteins). Results showed that FMN improved lean mass, grip strength, mitochondrial membrane potential, and ATP production, while reducing ROS and ferroptosis by regulating ACSL4, GPX4, and SLC7A11. Mechanistically, FMN exerted protective effects via the SIRT1/PGC-1α pathway, which was partially attenuated by SIRT1 knockdown or Mito-C. Collectively, FMN alleviates age-related sarcopenia by targeting mitochondrial function and ferroptosis, providing potential targets for sarcopenia treatment.
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Ferroptosis has recently been identified as a critical mechanism underlying arsenic trioxide (ATO)–induced cardiotoxicity. This study aimed to determine whether Honokiol (HKL) protects against ATO‐induced cardiac injury by inhibiting ferroptosis and to investigate the role of the SIRT3 signaling pathway in this process. Using 129S1/SvImJ wild‐type (WT) and SIRT3‐knockout (SIRT3−/−) mice, we demonstrated that HKL attenuates ATO‐induced myocardial injury and hypertrophy in a SIRT3‐dependent manner. Mechanistically, HKL reduced oxidative stress through the SIRT3/SOD2 pathway, as evidenced by decreased mitochondrial ROS production and SOD2 acetylation, along with preserved mitochondrial ATP generation capacity. Furthermore, HKL inhibited ferroptosis, indicated by reduced iron content, MDA levels, and 4‐HNE expression, along with restored GPX4 and GSH levels. Notably, HKL restored autophagic flux impaired by ATO, and this effect was associated with its antiferroptotic and cardioprotective actions. Pharmacological or genetic inhibition of SIRT3 or autophagic flux abolished the protective effects of HKL. Autophagic flux is closely associated with the protective effect of Honokiol on ATO‐induced ferroptosis. These findings reveal that HKL protects against ATO‐induced cardiomyopathy by restoring autophagic flux and inhibiting ferroptosis via the SIRT3 signaling pathway.
Qingqing Wei, An-Liang Huang, Ning-Yi Liu et al.· Cardiology Research and Prac...· 0 citations
Emerging evidence implicates ferroptosis in myocardial ischemic injury. This study aimed to investigate whether empagliflozin (EMP) suppresses ferroptosis in acute myocardial infarction (AMI) via the AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (NRF2)/solute carrier family 7 member 11 (SLC7A11) pathway.Hypoxia/reoxygenation (H/R)-injured HL-1 cardiomyocytes were treated with EMP (10, 20, 30 μM). Cell viability, morphology, damage, and apoptosis were assessed by CCK-8, inverted microscopy, lactate dehydrogenase (LDH) release, and flow cytometry. H/R-injured cells were treated with 30 μM EMP and/or ferrostatin-1 (Fer-1), followed by measurements of Fe2+, malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS), superoxide dismutase (SOD), lipid ROS (C11-BODIPY), ferroptosis-related proteins [SLC7A11, glutathione peroxidase 4 (GPX4), phospho-AMPK (p-AMPK), AMPK, NRF2 using Western blot], and NRF2 nuclear translocation (using immunofluorescence). An AMI mouse model was established. Myocardial pathology and infarct size were evaluated, and AMPK/NRF2/SLC7A11 pathway proteins and myocardial Fe2+/MDA/GSH levels were measured.EMP partially reversed H/R-induced cardiomyocyte shrinkage and membrane rupture, reduced viability, elevated LDH, and increased apoptosis. Among cell death inhibitors, Fer-1 exerted maximal protection, indicating ferroptosis may be the predominant death type in H/R-injured HL-1 cardiomyocytes. EMP mirrored the anti-ferroptotic activity of Fer-1. Mechanistically, EMP decreased cytoplasmic NRF2 and the p-AMPK/AMPK ratio while promoting the translocation of NRF2 from the cytoplasm to the nucleus. EMP activated the AMPK/NRF2/SLC7A11 axis to attenuate ferroptosis in AMI mice.In conclusion, EMP suppressed ferroptosis and ameliorated cellular injury in H/R-injured cardiomyocytes by activating the AMPK/NRF2/SLC7A11 pathway, with efficacy confirmed in vivo during AMI.
