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

OBJECTIVES

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.

METHODS

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

RESULTS

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 Fe levels, while increasing glutathione (GSH) content in cardiomyocytes.

CONCLUSION

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.