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Background <p>Ferroptosis is a form of regulated cell death (RCD) characterized by accumulation of lipid peroxides and dependence on iron. However, the role of ferroptosis in sepsis-induced myocardial injury remains unclear.</p> Methods and <p><b>Results</b> Here, we used the cecal ligation and puncture (CLP) model to induce the onset of myocardial injury in sepsis mice, and established an iron overload model as positive control group to explore the specific effects of iron overload on myocardium and explore the mechanism of sepsis induced myocardial injury. The results showed that in the CLP group, the levels of myocardial injury markers --- cardiac troponin T (CTn-T), myocardial-bound creatine kinase (CK-MB), lactic dehydrogenase (LDH) were elevated, the levels of oxidative stress markers ---- malondialdehyde (MDA) and reactive oxygen species (ROS) levels were increased, the levels of the antioxidant enzymes superoxide dismutase (SOD) and the anti-ferroptosis markers ---- glutathione peroxidase 4 (GPX4), the solute carrier family-7 member-11 (SLC7A11/ xCT), ferroptosis suppressor protein-1(FSP1), and lipin-1 (LPIN1) were decreased, lipocalin 2 (Lcn2) protein expression and signal transducer and activator of transcription 3 (STAT3) phosphorylation were increased, mitochondria damage was observed when compared with the sham group. All above results were attenuated by ferrostatin-1 (Fer-1, a ferroptosis inhibitor) and dexrazoxane hydrochloride (DXZ, an iron chelator). Meanwhile, acute iron overload injury caused by iron dextran was consistent with the CLP group. We also found Transferrin Receptor1 (TFR1) protein expression was increased and the expressions of ferritin and ferroprotein 1 (FPN1) proteins were decreased in the CLP and iron dextran groups in contrast to the control group, indicating accumulation of intracellular iron occurred in the CLP and iron dextran groups.</p> Conclusion <p>Based on these findings, we concluded that iron overload and ferroptosis are maybe the key mechanisms underlying CLP-induced myocardial injury in septic mice. STAT3/Lcn2 may involve in regulating iron overload and ferroptosis, and performs as a potential therapy target in sepsis-induced myocardial injury.</p>

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Inhibition of iron overload and ferroptosis attenuates sepsis-induced myocardial injury in mice through STAT3/Lcn2 pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月15日

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  • Yuhui Huang,
  • Linlin Zhang,
  • Yiren Wang,
  • Yuying He,
  • Ruoli Du,
  • Qi Yun,
  • Qin Gao,
  • Hongwei Ye

摘要

Background

Ferroptosis is a form of regulated cell death (RCD) characterized by accumulation of lipid peroxides and dependence on iron. However, the role of ferroptosis in sepsis-induced myocardial injury remains unclear.

Methods and

Results Here, we used the cecal ligation and puncture (CLP) model to induce the onset of myocardial injury in sepsis mice, and established an iron overload model as positive control group to explore the specific effects of iron overload on myocardium and explore the mechanism of sepsis induced myocardial injury. The results showed that in the CLP group, the levels of myocardial injury markers --- cardiac troponin T (CTn-T), myocardial-bound creatine kinase (CK-MB), lactic dehydrogenase (LDH) were elevated, the levels of oxidative stress markers ---- malondialdehyde (MDA) and reactive oxygen species (ROS) levels were increased, the levels of the antioxidant enzymes superoxide dismutase (SOD) and the anti-ferroptosis markers ---- glutathione peroxidase 4 (GPX4), the solute carrier family-7 member-11 (SLC7A11/ xCT), ferroptosis suppressor protein-1(FSP1), and lipin-1 (LPIN1) were decreased, lipocalin 2 (Lcn2) protein expression and signal transducer and activator of transcription 3 (STAT3) phosphorylation were increased, mitochondria damage was observed when compared with the sham group. All above results were attenuated by ferrostatin-1 (Fer-1, a ferroptosis inhibitor) and dexrazoxane hydrochloride (DXZ, an iron chelator). Meanwhile, acute iron overload injury caused by iron dextran was consistent with the CLP group. We also found Transferrin Receptor1 (TFR1) protein expression was increased and the expressions of ferritin and ferroprotein 1 (FPN1) proteins were decreased in the CLP and iron dextran groups in contrast to the control group, indicating accumulation of intracellular iron occurred in the CLP and iron dextran groups.

Conclusion

Based on these findings, we concluded that iron overload and ferroptosis are maybe the key mechanisms underlying CLP-induced myocardial injury in septic mice. STAT3/Lcn2 may involve in regulating iron overload and ferroptosis, and performs as a potential therapy target in sepsis-induced myocardial injury.