Parthenolide alleviates sepsis-induced acute lung injury in rat models by regulating the ferroptosis pathway

doi:10.16352/j.issn.1001-6325.2026.09.1207

Abstract

Abstract: Objective To explore the effect of parthenolide (PTL) on sepsis-induced acute lung injury (ALI) through nuclear factor erythroid 2-related factor 2-glutathione peroxidase 4 (Nrf2-GPX4) ferroptosis pathway. Methods The cecal ligation and puncture (CLP) method was used to construct an ALI rat model. Rats were randomly divided into control group, ALI group, ALI+PTL group, ALI+Nrf2 agonist (SFN) group, and ALI+PTL+Nrf2 inhibitor (ML385) group. Blood gas indicators and pulmonary edema were evaluated by Blood gas analyzer and lung wet/dry weight ratio. HE staining and Perls staining microscopy were used to identify the pathological characteristics. ELISA and immunofluorescence were performed to measure oxidative stress and iron metabolism indicators. Western blot was performed to detect the Nrf2-GPX4 pathway related proteins. Results ALI group, ALI+PTL group and ALI+SFN group all showed up-regulation of partial arterial pressure of oxygen(PaO₂), superoxide dismutase(SOD) activity, glutathione peroxidase(GSH-Px) activity, glutathione peroxidase 4(GPX4) positive cell rate, p-Nrf2/Nrf2 ratio, and GPX4 protein, but down-regulation of partial arterial pressure of carbon dioxide(PaCO₂), lung wet/dry weight ratio, lung tissue pathological injury score, iron deposition area percentage, 4-hydroxynonenal(4-HNE) content, 8-hydroxy-2-deoxyguanosine(8-OHdG) content, acyl-CoA synthetase long-chain family member 4(ACSL4) positive cell rate, ferritin positive cell rate and heme oxygenase-1(HO-1) protein(P＜0.05). In ALI+PTL group and ALI+PTL+ML385 group indicators mentioned above were all significantly reversed(P＜0.05). Conclusions PTL alleviates sepsis-induced ALI by a mechanism of activation of Nrf2-GPX4 pathway.

Key words: parthenolide, ferroptosis pathway, sepsis, acute lung injury

CLC Number:

R563
R363.2

ZHANG Lulu, TIAN Hui. Parthenolide alleviates sepsis-induced acute lung injury in rat models by regulating the ferroptosis pathway[J]. Basic & Clinical Medicine, 2026, 46(9): 1207-1212.

References

[1] Zhang J, Yan W, Dong Y, et al. Early identification and diagnosis, pathophysiology, and treatment of sepsis-related acute lung injury: a narrative review[J]. J Thorac Dis, 2024, 16:5457-5476. doi: 10.21037/jtd-24-1191.
[2] Xu Y, Xin J, Sun Y, et al. Mechanisms of sepsis-induced acute lung injury and advancements of natural small molecules in its treatment[J]. Pharmaceuticals (Basel), 2024, 17:472-489. doi: 10.3390/ph17040472.
[3] Zhang J, Zhu X, Li Y, et al. Parthenolide improves sepsis-induced coagulopathy by inhibiting mitochondrial-mediated apoptosis in vascular endothelial cells through BRD4/BCL-xL pathway[J]. J Transl Med, 2025, 23:80-96. doi: 10.1186/s12967-025-06114-0.
[4] 郝丹丹, 张垒, 白春英. 靶向铁死亡治疗非酒精性脂肪性肝病的研究进展[J]. 基础医学与临床, 2023, 43:1317-1321. doi:10.16352/j.issn.1001-6325.2023.08.1317.
[5] Zheng Q, Xing J, Li X, et al. PRDM16 suppresses ferroptosis to protect against sepsis-associated acute kidney injury by targeting the NRF2/GPX4 axis[J]. Redox Biol, 2024, 78:103417-103429. doi: 10.1016/j.redox.2024.103417.
[6] Xie C, Wang T, Liu A, et al. Sirt4 overexpression modulates the JAK2/STAT3 and PI3K/AKT/mTOR axes to alleviate sepsis-induced acute lung injury[J]. Cell Biochem Biophys, 2025, 83:1785-1798. doi: 10.1007/s12013-024-01588-z.
[7] Elseweidy MM, Harb NG, Ali AA, et al. Sulforaphane substantially impedes testicular ferroptosis in adult rats exposed to di-2-ethylhexyl phthalate through activation of NRF-2/SLC7A11/GPX-4 trajectory[J]. Naunyn Schmiedebergs Arch Pharmacol, 2025, 39:3163-3175. doi: 10.1007/s00210-024-03440-w.
[8] Han Y, Li W, Duan H, et al. Ligustrazine hydrochloride prevents ferroptosis by activating the NRF2 signaling pathway in a high-altitude cerebral edema rat model[J]. Int J Mol Sci, 2025, 26:1110-1121. doi: 10.3390/ijms26031110.
[9] Shou DW, Li YR, Xu XJ, et al. Parthenolide attenuates sepsis-induced acute kidney injury in rats by reducing inflammation[J]. Evid Based Complement Alternat Med, 2023, 2023:8759766-8759784. doi: 10.1155/2023/8759766.
[10] Albalawi RS, Binmahfouz LS, Hareeri RH, et al. Parthenolide phytosomes attenuated gentamicin-induced nephrotoxicity in rats via activation of Sirt-1, Nrf2, OH-1, and NQO1 axis[J]. Molecules, 2023, 28:2741-2759. doi: 10.3390/molecules28062741.
[11] Wang XX, Li M, Xu XW, et al. BNIP3-mediated mitophagy attenuates hypoxic-ischemic brain damage in neonatal rats by inhibiting ferroptosis through p62-KEAP1-NRF2 pathway activation to maintain iron and redox homeostasis[J]. Acta Pharmacol Sin, 2025, 46:33-51. doi: 10.1038/s41401-024-01365-x.
[12] Zhang H, Wang Y, Wang S, et al. Tangeretin alleviates sepsis-induced acute lung injury by inhibiting ferroptosis of macrophage via Nrf2 signaling pathway[J]. Chin Med, 2025, 20:11-25. doi: 10.1186/s13020-025-01063-8.

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