MST1 participates in the pathogenesis of sepsis-induced acute lung injury through regulation of Nrf2/HO-1 pathway_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

YANG Lili ¹ , WANG Yanyan ² ,  YU Honglian ³

1. School of Basic Medical Sciences, Shandong Second Medical University, Weifang , Shandong 261053, P. R. China;
2. Department of paediatrics, Weifang Maternal and Child Health Hospital, Weifang, Shandong 261000, P. R. China;
3. Biochemistry and Molecular Biology Teaching and Research Office, Jining Medical University, Jining, Shandong 272067, P. R. China;

Corresponding?author：

YU Honglian, Email: yuhonglian@mail.jnmc.edu.cn

Keywords：

Sepsis; acute lung injury; STE20-like kinase 1; nuclear factor-erythroid 2 related factor 2; heme oxygenase 1; oxidative stress

DOI：

10.7507/1671-6205.202507129

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Objective To investigate the role of mammalian STE20-like kinase 1 (MST1) in sepsis-induced acute lung injury (ALI) and its molecular mechanisms in regulating the nuclear factor-erythroid 2 related factor 2 (Nrf2)/heme oxygenase 1(HO-1) antioxidant signaling pathway. Methods A murine sepsis-induced ALI model was established by intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg). Lung injury was assessed by hematoxylin-eosin (HE) staining, lung injury scoring, and bronchoalveolar lavage fluid (BALF) analysis. Mst1 knockout mice and RAW264.7 macrophages were used. Related proteins and inflammatory factors were detected by Western blot, qRT-PCR, immunofluorescence, and ELISA. The regulatory relationship of the Mst1-Nrf2/HO-1 signaling axis was verified using siRNA knockdown and overexpression techniques combined with Nrf2 inhibitor and activator treatments. Results After LPS treatment, mouse lung tissues showed typical ALI pathological changes, and Mst1 protein expression was upregulated in a time-dependent manner. Mst1 deficiency significantly alleviated lung injury and reduced protein concentration and inflammatory cell counts in BALF. In vitro experiments showed that Mst1 knockdown in RAW264.7 macrophages inhibited LPS-induced secretion of tumor necrosis factor-α, interleukin-6, and interleukin-1β. Mechanistic studies revealed that Mst1 promoted oxidative stress and inflammatory responses by inhibiting Nrf2 nuclear translocation and HO-1 expression. Nrf2 inhibitor partially reversed the protective effects of Mst1 knockdown, while the Nrf2 activator tBHQ significantly improved lung injury. Conclusions Mst1 promotes the development of sepsis-induced ALI through negative regulation of the Nrf2/HO-1 antioxidant signaling pathway. Mst1 may serve as a potential therapeutic target for sepsis-induced ALI.

Citation： YANG Lili, WANG Yanyan, YU Honglian. MST1 participates in the pathogenesis of sepsis-induced acute lung injury through regulation of Nrf2/HO-1 pathway. Chinese Journal of Respiratory and Critical Care Medicine, 2026, 25(5): 342-350. doi: 10.7507/1671-6205.202507129 Copy

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2.	Ding YH, Song YD, Wu YX, et al. Isoalantolactone suppresses LPS-induced inflammation by inhibiting TRAF6 ubiquitination and alleviates acute lung injury. Acta Pharmacol Sin, 2019, 40(1): 64-74.
3.	戴成, 王毅, 于湘友. 亞甲藍治療對膿毒癥大鼠肺臟誘導型一氧化氮合酶變化的影響. 中華危重病急救醫學, 2016(2): 134-139.
4.	Sun L, Liu Y, Liu X, et al. Nano-enabled reposition of proton pump inhibitors for TLR inhibition: toward a new targeted nanotherapy for acute lung injury. Adv Sci (Weinh), 2022, 9(3): e2104051.
5.	Li X, Cui L, Feng G, et al. Collagen peptide promotes DSS-induced colitis by disturbing gut microbiota and regulation of macrophage polarization. Front Nutr, 2022, 9: 957391.
6.	Jiang W, Ma C, Bai J, et al. Macrophage SAMSN1 protects against sepsis-induced acute lung injury in mice. Redox Biol, 2024, 73: 103226.
7.	Fuenzalida B, Kallol S, Zaugg J, et al. Primary human trophoblasts mimic the preeclampsia phenotype after acute hypoxia-reoxygenation insult. Cells, 2022, 11(12): 1898.
8.	Shin DU, Eom JE, Song HJ, et al. Camellia sinensis L. alleviates pulmonary inflammation induced by porcine pancreas elastase and cigarette smoke extract . Antioxidants (Basel), 2022, 11(9): 1683.
9.	Feng Y, Guo X, Tian H, et al. Induction of HOXA3 by porcine reproductive and respiratory syndrome virus inhibits type I interferon response through negative regulation of HO-1 transcription. J Virol, 2022, 96(3): e0186321.
10.	陶新, 徐逸, 宋志文, 等. Hippo信號通路參與脊髓損傷的調控. 中國組織工程研究, 2023, 27(4): 619-625.
11.	Cho KM, Kim MS, Jung HJ, et al. Mst1-deficiency induces hyperactivation of monocyte-derived dendritic cells via Akt1/c-myc pathway. Front Immunol, 2019, 10: 2142.
12.	Du X, Shi H, Li J, et al. Mst1/Mst2 regulate development and function of regulatory T cells through modulation of Foxo1/Foxo3 stability in autoimmune disease. J Immunol, 2014, 192(4): 1525-1535.
13.	Matute-Bello G, Downey G, Moore BB, et al. An official american thoracic society workshop report: Features and measurements of experimental acute lung injury in animals. Am J Respir Cell Mol Biol, 2011, 44(5): 725-738.
14.	趙哲, 穆培娟, 張冬. SAPCD2對肺腺癌A549細胞生物學功能的影響及機制研究. 中國呼吸與危重監護雜志, 2023, 22(7): 506-514.
15.	Attarha S, Andersson S, Mints M, et al. Mammalian sterile-like 1 kinase inhibits TGFβ and EGF dependent regulation of invasiveness, migration and proliferation of HEC-1-A endometrial cancer cells. Int J Oncol, 2014, 45(2): 853-860.
16.	Ni M, Qiu J, Liu G, et al. Loss of macrophage TSC1 exacerbates sterile inflammatory liver injury through inhibiting the AKT/MST1/NRF2 signaling pathway. Cell Death Dis, 2024, 15(2): 146.
17.	Wang P, Geng J, Gao J, et al. Macrophage achieves self-protection against oxidative stress-induced ageing through the Mst-Nrf2 axis. Nat Commun, 2019, 10(1): 755.
18.	Zhang C, Zhao Y, Yang X. Azilsartan attenuates lipopolysaccharide-induced acute lung injury via the Nrf2/HO-1 signaling pathway. Immunol Res, 2022, 70(1): 97-105.
19.	董文平, 任壽安. 血清核轉錄因子紅系2相關因子2、血紅素加氧酶-1水平與阻塞性睡眠呼吸暫停患者認知障礙的相關性研究. 中國呼吸與危重監護雜志, 2022, 21(7): 478-483.
20.	Nathan C, Cunningham-Bussel A. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal, 2014, 20(7): 1126-1167.
21.	Morgan MJ, Liu ZG. Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res, 2011, 21(1): 103-115.
22.	Fan F, He Z, Kong LL, et al. Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration. Sci Transl Med, 2016, 8(352): 352ra108.

1. Li Z, Liu T, Feng Y, et al. PPARγ alleviates sepsis-induced liver injury by inhibiting hepatocyte pyroptosis via inhibition of the ROS/TXNIP/NLRP3 signaling pathway. Oxid Med Cell Longev, 2022: 1269747.
2. Ding YH, Song YD, Wu YX, et al. Isoalantolactone suppresses LPS-induced inflammation by inhibiting TRAF6 ubiquitination and alleviates acute lung injury. Acta Pharmacol Sin, 2019, 40(1): 64-74.
3. 戴成, 王毅, 于湘友. 亞甲藍治療對膿毒癥大鼠肺臟誘導型一氧化氮合酶變化的影響. 中華危重病急救醫學, 2016(2): 134-139.
4. Sun L, Liu Y, Liu X, et al. Nano-enabled reposition of proton pump inhibitors for TLR inhibition: toward a new targeted nanotherapy for acute lung injury. Adv Sci (Weinh), 2022, 9(3): e2104051.
5. Li X, Cui L, Feng G, et al. Collagen peptide promotes DSS-induced colitis by disturbing gut microbiota and regulation of macrophage polarization. Front Nutr, 2022, 9: 957391.
6. Jiang W, Ma C, Bai J, et al. Macrophage SAMSN1 protects against sepsis-induced acute lung injury in mice. Redox Biol, 2024, 73: 103226.
7. Fuenzalida B, Kallol S, Zaugg J, et al. Primary human trophoblasts mimic the preeclampsia phenotype after acute hypoxia-reoxygenation insult. Cells, 2022, 11(12): 1898.
8. Shin DU, Eom JE, Song HJ, et al. Camellia sinensis L. alleviates pulmonary inflammation induced by porcine pancreas elastase and cigarette smoke extract . Antioxidants (Basel), 2022, 11(9): 1683.
9. Feng Y, Guo X, Tian H, et al. Induction of HOXA3 by porcine reproductive and respiratory syndrome virus inhibits type I interferon response through negative regulation of HO-1 transcription. J Virol, 2022, 96(3): e0186321.
10. 陶新, 徐逸, 宋志文, 等. Hippo信號通路參與脊髓損傷的調控. 中國組織工程研究, 2023, 27(4): 619-625.
11. Cho KM, Kim MS, Jung HJ, et al. Mst1-deficiency induces hyperactivation of monocyte-derived dendritic cells via Akt1/c-myc pathway. Front Immunol, 2019, 10: 2142.
12. Du X, Shi H, Li J, et al. Mst1/Mst2 regulate development and function of regulatory T cells through modulation of Foxo1/Foxo3 stability in autoimmune disease. J Immunol, 2014, 192(4): 1525-1535.
13. Matute-Bello G, Downey G, Moore BB, et al. An official american thoracic society workshop report: Features and measurements of experimental acute lung injury in animals. Am J Respir Cell Mol Biol, 2011, 44(5): 725-738.
14. 趙哲, 穆培娟, 張冬. SAPCD2對肺腺癌A549細胞生物學功能的影響及機制研究. 中國呼吸與危重監護雜志, 2023, 22(7): 506-514.
15. Attarha S, Andersson S, Mints M, et al. Mammalian sterile-like 1 kinase inhibits TGFβ and EGF dependent regulation of invasiveness, migration and proliferation of HEC-1-A endometrial cancer cells. Int J Oncol, 2014, 45(2): 853-860.
16. Ni M, Qiu J, Liu G, et al. Loss of macrophage TSC1 exacerbates sterile inflammatory liver injury through inhibiting the AKT/MST1/NRF2 signaling pathway. Cell Death Dis, 2024, 15(2): 146.
17. Wang P, Geng J, Gao J, et al. Macrophage achieves self-protection against oxidative stress-induced ageing through the Mst-Nrf2 axis. Nat Commun, 2019, 10(1): 755.
18. Zhang C, Zhao Y, Yang X. Azilsartan attenuates lipopolysaccharide-induced acute lung injury via the Nrf2/HO-1 signaling pathway. Immunol Res, 2022, 70(1): 97-105.
19. 董文平, 任壽安. 血清核轉錄因子紅系2相關因子2、血紅素加氧酶-1水平與阻塞性睡眠呼吸暫停患者認知障礙的相關性研究. 中國呼吸與危重監護雜志, 2022, 21(7): 478-483.
20. Nathan C, Cunningham-Bussel A. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal, 2014, 20(7): 1126-1167.
21. Morgan MJ, Liu ZG. Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res, 2011, 21(1): 103-115.
22. Fan F, He Z, Kong LL, et al. Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration. Sci Transl Med, 2016, 8(352): 352ra108.

Chinese Journal of Respiratory and Critical Care Medicine

MST1 participates in the pathogenesis of sepsis-induced acute lung injury through regulation of Nrf2/HO-1 pathway

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