Stachydrine Alleviates Sepsis-Induced Cardiomyopathy by Inhibiting Ferroptosis via Regulating SIRT1/GPX4 Pathway

This study investigated the cardioprotective effects of stachydrine (STA) in lipopolysaccharide (LPS)-induced septic mice and H9c2 cardiomyocytes, focusing on its anti-apoptotic, anti-inflammatory, and anti-ferroptotic actions.

We established an LPS-induced sepsis model in mice and an LPS-stimulated H9c2 cardiomyocyte model in vitro.

STA markedly reduced LPS-induced myocardial apoptosis, as demonstrated by decreased TUNEL-positive cells, and attenuated the elevation of serum cardiac injury markers, including creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), brain natriuretic peptide (BNP), cardiac troponin I (cTnI), and cardiac troponin T (cTnT) levels. STA also suppressed systemic inflammation, significantly reducing interleukin-1 beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α) levels at both mRNA and protein levels. Additionally, STA significantly inhibited LPS-induced production of pro-inflammatory cytokines in H9c2 cardiomyocytes. Mechanistically, STA activated the SIRT1/Nrf2 signaling axis and enhanced the expression of ferroptosis-related proteins, solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). Additionally, STA reduced oxidative stress and iron accumulation by decreasing malondialdehyde (MDA), Total Fe, and Fe²⁺ levels, while increasing glutathione (GSH) content in cardiomyocytes.

Our results suggest that STA confers robust cardioprotective effects in LPS-induced models by mitigating apoptosis, inflammation, and ferroptosis, partly via SIRT1/GPX4 pathway activation.