The Protective Role of GPER Against Endotoxin-Induced Hepatocyte Injury via Disruption of Oxidative Stress-Inflammation Cycle

doi:10.3870/j.issn.1672-8009.2026.03.002

Abstract

Abstract: Objective To investigate the protective effect of the G protein-coupled estrogen receptor(GPER)against endotoxin-induced hepatocyte injury and its underlying molecular mechanism,and to evaluate its potential as a sex-specific therapeutic strategy. Methods An AML-12 mouse hepatocyte model induced by lipopolysaccharide(LPS)was used to simulate the early pathological processes of septic liver injury.The cells were divided into four groups:blank control,LPS,LPS+G1(a GPER agonist),and LPS+G15(a GPER antagonist).Techniques including flow cytometry,Western blot,RT-qPCR,ELISA,and transmission electron microscopy were employed to assess apoptosis rate,GPER expression,mtROS,MDA,NLRP3 inflammasome activation,IL-1β levels,ATP/AMP ratio,ΔΨm,and ultrastructural changes. Results Compared with the LPS group,G1 treatment significantly reduced the apoptosis rate,suppressed mtROS and MDA production,downregulated the NLRP3/Caspase-1/IL-1β signaling pathway,increased ATP level,decreased the AMP/ATP ratio,and ameliorated mitochondrial membrane potential and ultrastructure.In contrast,G15 exacerbated these injuries.Correlation analysis showed that GPER expression was negatively correlated with the apoptosis rate(R²=0.8970),while mtROS levels were positively correlated with both apoptosis rate and IL-1β content. Conclusion GPER activation alleviates septic liver injury by inhibiting mtROS production,blocking NLRP3 inflammasome activation and subsequent inflammatory responses,and improving mitochondrial energy metabolism and structural integrity.This mechanism provides a novel target and theoretical basis for sex-specific treatment strategies in clinical practice.

Key words: septic liver injury, G protein-coupled estrogen receptor, oxidative stress, NLRP3 inflammasome, mitochondrial dysfunction, gender difference

CLC Number:

R631.2

YANG Leilei, PENG Jian, FENG Xiaojing, GAO Shan, CHEN Zhen. The Protective Role of GPER Against Endotoxin-Induced Hepatocyte Injury via Disruption of Oxidative Stress-Inflammation Cycle[J]. Journal of Medical Molecular Biology, 2026, 23(3): 242-249.

References

[1] FLEISCHMANN-STRUZEK C,MELLHAMMAR L,ROSE N,et al.Incidence and mortality of hospital-and ICU-treated sepsis:Results from an updated and expanded systematic review and meta-analysis[J].Intensive Care Med,2020,46(8):1552-1562.
[2] XU X,YANG T,AN J,et al.Liver injury in sepsis:Manifestations,mechanisms and emerging therapeutic strategies[J].Front Immunol,2025,16:1575554.
[3] SRDIĆ T,ÐURAŠEVIĆ S,LAKIĆ I,et al.From molecular mechanisms to clinical therapy:Understanding sepsis-induced multiple organ dysfunction[J].Int J Mol Sci,2024,25(14):7770.
[4] KARKI R,KANNEGANTI T D.The ’cytokine storm’:Molecular mechanisms and therapeutic prospects[J].Trends Immunol,2021,42(8):681-705.
[5] MELIN N,YARAHMADOV T,SANCHEZ-TALTAVULL D,et al.A new mouse model of radiation-induced liver disease reveals mitochondrial dysfunction as an underlying fibrotic stimulus[J].JHEP Rep,2022,4(7):100508.
[6] HU J,XIE S,LIAO Y,et al.The gender paradox in sepsis:Exploring male vulnerability and female resilience[J].Am J Surg,2025,247:116293.
[7] PARK G,MUNLEY J A,KELLY L S,et al.Gut mycobiome dysbiosis after sepsis and trauma[J].Crit Care,2024,28(1):18.
[8] SON S E,IM D S.Activation of G protein-coupled estrogen receptor 1(GPER)attenuates obesity-induced asthma by switching M1 macrophages to M2 macrophages[J].Int J Mol Sci,2024,25(17):9532.
[9] LIU D,HUANG S Y,SUN J H,et al.Sepsis-induced immunosuppression:Mechanisms,diagnosis and current treatment options[J].Mil Med Res,2022,9(1):56.
[10] MEWES C,RUNZHEIMER J,BÖHNKE C,et al.Association of sex differences with mortality and organ dysfunction in patients with sepsis and septic shock[J].J Pers Med,2023,13(5):836.
[11] ADU-AMANKWAAH J,ADEKUNLE A O,TANG Z,et al.Estradiol contributes to sex differences in resilience to sepsis-induced metabolic dysregulation and dysfunction in the heart via GPER-1-mediated PPARδ/NLRP3 signaling[J].Metabolism,2024,156:155934.
[12] LI Z,CHEN L,CHU H,et al.Estrogen alleviates hepatocyte necroptosis depending on GPER in hepatic ischemia reperfusion injury[J].J Physiol Biochem,2022,78(1):125-137.
[13] ZHAO M,WANG Y,LI L,et al.Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance[J].Theranostics,2021,11(4):1845-1863.
[14] KONG H,ZHAO H,CHEN T,et al.Targeted P2 X7/NLRP3 signaling pathway against inflammation,apoptosis,and pyroptosis of retinal endothelial cells in diabetic retinopathy[J].Cell Death Dis,2022,13(4):336.
[15] XIAN H,WATARI K,SANCHEZ-LOPEZ E,et al.Oxidized DNA fragments exit mitochondria via mPTP-and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling[J].Immunity,2022,55(8):1370-1385.e8.
[16] MA S,CHEN J,FENG J,et al.Melatonin ameliorates the progression of atherosclerosis via mitophagy activation and NLRP3 inflammasome inhibition[J].Oxid Med Cell Longev,2018,2018:9286458.
[17] LEE D J,DU F,CHEN S W,et al.Regulation and function of the caspase-1 in an inflammatory microenvironment[J].J Invest Dermatol,2015,135(8):2012-2020.
[18] LI L,WANG H,YAO Y,et al.The sex steroid precursor dehydroepiandrosterone prevents nonalcoholic steatohepatitis by activating the AMPK pathway mediated by GPR30[J].Redox Biol,2021,48:102187.
[19] 阮培森,郑耀,董卓亚,等.AMPK信号通道调节自噬和线粒体稳态的研究进展[J].中华危重病急救医学,2024,36(4):425-429.
RUAN P S,ZHENG Y,DONG Z Y,et al.Research progress in the regulation of autophagy and mitochondrial homeostasis by AMPK signaling channels[J].Chin Crit Care Med,2024,36(4):425-429.