熊果酸通过Nrf2/GPX4信号通路对稀土氧化钕所致肝损伤的改善作用

doi:10.3969/j.issn.1006-5725.2026.03.005

Abstract

Abstract:

Objective To investigate the effect of ursolic acid on liver injury induced by neodymium oxide in rats based on the Nrf2/GPX4 signaling pathway and explore its underlying mechanism. Methods Sixty 6-week-old specific pathogen-free （SPF） grade Sprague-Dawley （SD） rats were randomly allocated into six groups （n = 10 per group）： a blank control group， a neodymium oxide model group， low-dose， medium-dose， and high-dose ursolic acid groups， and a diammonium glycyrrhizinate group. After a 9-week intervention period， the rats were fasted for 12 hours with free access to water prior to sacrifice. Hepatic histopathology was examined using hematoxylin and eosin （HE） staining. Serum biochemical markers of liver function were assayed. The levels of superoxide dismutase （SOD）， malondialdehyde （MDA）， glutathione peroxidase （GSH-Px）， tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， and interleukin-10 （IL-10） were detected by enzyme-linked immunosorbent assay （ELISA）. The Fe2? content in the liver was determined through colorimetry. The protein expression levels of nuclear factor erythroid 2-related factor 2 （Nrf2） and glutathione peroxidase 4 （GPX4） in liver tissue were measured by Western blotting. Results In comparison with the normal control group， the model group exhibited fatty vacuoles of varying sizes and extensive infiltration of inflammatory cells in the liver tissue. The activities of serum alanine aminotransferase （ALT） and aspartate aminotransferase （AST）， the levels of malondialdehyde （MDA）， tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， and the content of Fe2? were significantly elevated （P < 0.05）， whereas the levels of superoxide dismutase （SOD）， glutathione peroxidase （GSH-Px）， and interleukin-10 （IL-10） were significantly decreased （P < 0.05）. After the intervention of ursolic acid， hepatic steatosis was remarkably improved， and the infiltration of inflammatory cells was reduced. The activities of serum ALT and AST， the levels of MDA， TNF-α， IL-1β， and the content of Fe2? were significantly decreased （P < 0.05）， while the levels of SOD， GSH-Px， and IL-10 were significantly increased （P < 0.05）. Western blot results indicated that， when compared with the normal control group， the protein expression of nuclear factor erythroid 2-related factor 2 （Nrf2） and glutathione peroxidase 4 （GPX4） in the liver of the model group was significantly reduced （P < 0.05）. Nevertheless， after the intervention of ursolic acid， the expression of Nrf2 and GPX4 proteins was significantly increased （P < 0.05）. Conclusion Ursolic acid exerts a protective effect against neodymium oxide-induced liver injury in rats. Its mechanism may be associated with the regulation of the Nrf2/GPX4 signaling pathway， which can reduce the inflammatory response， alleviate oxidative stress， and consequently inhibit ferroptosis.

Key words: eridictyronic acid, neodymium oxide, liver injury, Nrf2/GPX4 signaling pathway, oxidative stress, ferroptosis

CLC Number:

R-15

Jiaxin LIU,Mengqi SHI,Tengfei GUO,Xue ZHAO,Duo YIN,Wenlong ZHANG,Na GE,Yajing YUAN,Shuyu GE. The ameliorative effect of ursolic acid on liver injury induced by rare earth neodymium oxide through the Nrf2/GPX4 signaling pathway[J]. The Journal of Practical Medicine, 2026, 42(3): 387-394.

Figures/Tables 6

Fig.1

Tab.1

Fig.2

Fig.3

Fig.4

Fig.5

References 28

[1]	侯方鹏，范小娜，谢璐，等. 最常见的几种稀土元素对机体系统的影响［J］. 赣南医学院学报， 2022， 42（3）： 225-231. doi： 10. 3969/j. issn. 1001 -5779. 2022. 03. 002 . doi: 10. 3969/j. issn. 1001 -5779. 2022. 03. 002
[2]	LENG J， WANG N， CHANG X L， et al. Neodymium nitrate promotes the apoptosis of mouse liver cells via Bcl2l1/Caspase 3 pathway［J］. Toxicol Mech Methods， 2025， 35（8）： 993-1002. doi： 10.1080/15376516.2025.2501253 . doi: 10.1080/15376516.2025.2501253
[3]	AHMAD J， WAHAB R， SIDDIQUI M A， et al. Neodymium oxide nanostructures and their cytotoxic evaluation in human cancer cells［J］. J Trace Elem Med Biol， 2022， 73： 127029. doi： 10.1016/j.jtemb.2022.127029 . doi: 10.1016/j.jtemb.2022.127029
[4]	YANG D， SUI H， MAO W， et al. Dietary Exposure Assessment of Rare Earth Elements in the Chinese Population［J］. Int J Environ Res Public Health， 2022， 19（23）： 15583. doi： 10.3390/ijerph192315583 . doi: 10.3390/ijerph192315583
[5]	WANG N. Quantitative study on hepatic genotoxicity of neodymium and its molecular mechanisms based on Benchmark Dose method［J］. Front Pharmacol， 2024， 15： 1484111. doi： 10.3389/fphar.2024.1484111 . doi: 10.3389/fphar.2024.1484111
[6]	GWENZI W， MANGORI L， DANHA C， et al. Sources， behaviour， and environmental and human health risks of high-technology rare earth elements as emerging contaminants［J］. Sci Total Environ， 2018， 636： 299-313. doi： 10.1016/j.scitotenv. 2018.04.235 . doi: 10.1016/j.scitotenv. 2018.04.235
[7]	LUO X， WEI L， LIU S， et al. Correlation between urinary rare earth elements and liver function in a Zhuang population aged 35-74 years in Nanning［J］. J Trace Elem Med Biol， 2024， 84： 127426. doi： 10.1016/j.jtemb.2024.127426 . doi: 10.1016/j.jtemb.2024.127426
[8]	陈祖义，朱旭东. 稀土元素的肝脏蓄积性及毒性危害［J］. 家畜生态学报， 2009， 30（4）： 98-102. doi： 10.3969/j.issn.1673-1182.2009.04.026 . doi: 10.3969/j.issn.1673-1182.2009.04.026
[9]	MARGINSON H， MACMILLAN G A， GRANT E， et al. Rare earth element bioaccumulation and cerium anomalies in biota from the Eastern Canadian subarctic （Nunavik）［J］. Sci Total Environ， 2023， 879： 163024. doi： 10.1016/j.scitotenv. 2023. 163024 . doi: 10.1016/j.scitotenv. 2023. 163024
[10]	卜宁，王姝蕊，高艳荣，等. Keap1/Nf2/HO-1信号通路在稀土氧化钕致小鼠肝损伤中的作用［J］. 中华劳动卫生职业病杂志， 2023， 41（3）： 161-167. doi： 10.3760/cma.j.cn121094-20211206-00600 . doi: 10.3760/cma.j.cn121094-20211206-00600
[11]	WANG N， LENG J， HAN Y， et al. RNA-Seq Analysis of Mouse Hepatocytes AML12 Exposed to Neodymium Nitrate［J］. Toxics， 2025， 13（7）： 573. doi： 10.3390/toxics13070573 . doi: 10.3390/toxics13070573
[12]	李成成，李安丽，刘渝洪，等. 单羧酸转运蛋白1介导的乳酸堆积与铁死亡在急性肝衰竭中的正反馈机制［J］. 实用医学杂志， 2025， 41（22）： 3520-3528. doi： 10.3969/j.issn.1006-5725. 2025.22.008 . doi: 10.3969/j.issn.1006-5725. 2025.22.008
[13]	TANG D， CHEN X， KANG R， et al. Ferroptosis： Molecular mechanisms and health implications［J］. Cell Res， 2021， 31（2）： 107-125. doi： 10.1038/s41422-020-00441-1 . doi: 10.1038/s41422-020-00441-1
[14]	于蕙源，金令，于颖，等. 表儿茶素对对乙酰氨基酚诱导小鼠肝损伤的改善作用及其机制［J/OL］. 吉林大学学报（医学版）， 2025， 51（6）： 1-10. .
[15]	LIU J， WANG L， XIE M， et al. Varespladib attenuates Naja atra-induced acute liver injury via reversing Nrf2 signaling-mediated ferroptosis and mitochondrial dysfunction［J］. Redox Rep， 2025， 30（1）： 2507557. doi： 10.1080/13510002. 2025. 2507557 . doi: 10.1080/13510002. 2025. 2507557
[16]	OLAGNIER D， BRANDTOFT A M， GUNDERSTOFTE C， et al. Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming［J］. Nat Commun， 2018， 9（1）： 3506. doi： 10.1038/s41467-018-05861-7 . doi: 10.1038/s41467-018-05861-7
[17]	YANG D， ZHAI C， REN J， et al. Hydroxycitric acid inhibits ferroptosis and ameliorates benign prostatic hyperplasia by upregulating the Nrf2/GPX4 pathway［J］. World J Urol， 2025， 43（1）： 318. doi： 10.1007/s00345-025-05637-x . doi: 10.1007/s00345-025-05637-x
[18]	钱玲玲，吴卫明，金超. 黄连素调节GPX4干预非酒精性脂肪肝机制研究［J］. 药物生物技术， 2025， 32（2）： 156-160. doi： 10.19526/.cnki.1005-8915.20250206 . doi: 10.19526/.cnki.1005-8915.20250206
[19]	PEI J， WU M， CAI S， et al. The Protective Effect of Ursolic Acid on Unilateral Ureteral Obstruction in Rats by Activating the Nrf2/HO-1 Antioxidant Signaling Pathway［J］. Comput Intell Neurosci， 2022， 2022： 3690524. doi： 10.1155/2022/3690524 . doi: 10.1155/2022/3690524
[20]	张男男，戈娜. 熊果酸对实验性肝损伤的保护作用研究进展［J］. 华夏医学， 2018， 31（4）： 173-177. doi： 10.19296/j.cnki.1008-2409.2018-04-056 . doi: 10.19296/j.cnki.1008-2409.2018-04-056
[21]	GWENZI W， MANGORI L， DANHA C， et al. Sources， behaviour， and environmental and human health risks of high-technology rare earth elements as emerging contaminants［J］. Sci Total Environ， 2018， 636： 299-313. doi： 10.1016/j.scitotenv. 2018.04.235 . doi: 10.1016/j.scitotenv. 2018.04.235
[22]	薛瑾，陈应强. Nrf2/HO-1信号通路在肝脏相关疾病中的研究进展［J］. 南昌大学学报（医学版）， 2022， 62（3）： 88-92. doi：10.13764/j.cnki.ncdm.2022.03.017 . doi: 10.13764/j.cnki.ncdm.2022.03.017
[23]	WANG N， LENG J， XU J， et al. CircRNA_1156 Attenuates Neodymium Nitrate-Induced Hepatocyte Ferroptosis by Inhibiting the ACSL4/PKCβII Signaling Pathway［J］. Antioxidants （Basel）， 2025， 14（6）： 700. doi： 10.3390/antiox14060700 . doi: 10.3390/antiox14060700
[24]	XIONG L， HUANG J， WU C， et al. Yttrium chloride induces ferroptosis in cardiomyocytes via iron accumulation and triggers cardiac lipid peroxidation and inflammation that cause heart adverse events in mice［J］. Ecotoxicol Environ Saf， 2023， 263： 115279. doi： 10.1016/j.ecoenv.2023.115279 . doi: 10.1016/j.ecoenv.2023.115279
[25]	XIAO Z， GAO S， LI S， et al. Taohong Siwu Decoction modulates glutathione metabolism to suppress hepatocyte ferroptosis and demonstrates anti-fibrotic effects in the liver［J］. J Ethnopharmacol， 2025， 350： 120025. doi： 10.1016/j.jep.2025.120025 . doi: 10.1016/j.jep.2025.120025
[26]	GAO J， WANG S， TANG G， et al. Inflammation and accompanied disrupted hematopoiesis in adult mouse induced by rare earth element nanoparticles［J］. Sci Total Environ， 2022， 831： 155416. doi： 10.1016/j.scitotenv.2022.155416 . doi: 10.1016/j.scitotenv.2022.155416
[27]	DUAN J， PEI F， MIAO J， et al. Swietenine improved the progression of diabetic nephropathy through inhibiting ferroptosis via activating Akt/GSK-3β/Nrf2 signaling pathway［J］. J Ethnopharmacol， 2025， 349： 119981. doi： 10.1016/j.jep.2025.119981 . doi: 10.1016/j.jep.2025.119981
[28]	何俊荣，刘仔，陈锡培. 布洛芬对缺血性脑中风大鼠的神经保护作用及对Nrf2/SLC7A11/GPX4信号通路的影响［J］. 实用医学杂志， 2023， 39（15）： 1888-1892. doi：10.3969/j.issn.1006-5725.2023.15.006 . doi: 10.3969/j.issn.1006-5725.2023.15.006

组别	ALT/（U/mL）	AST/（U/mL）
空白对照组	1.26 ± 0.39	2.46 ± 0.25
Nd₂O₃模型组	1.96 ± 0.36^a	3.82 ± 0.19^a
UA低剂量组	1.69 ± 0.45	3.45 ± 0.77
UA中剂量组	1.32 ± 0.54^b	3.03 ± 0.62^b
UA高剂量组	1.28 ± 0.22^b	2.69 ± 0.36^b
DG组	1.33 ± 0.43^b	3.03 ± 0.74^b

The ameliorative effect of ursolic acid on liver injury induced by rare earth neodymium oxide through the Nrf2/GPX4 signaling pathway

RichHTML

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 6

References 28

Related Articles 15

Recommended Articles

Metrics

Comments

[1]	Lixia ZHANG,Xuefei FAN,Suhuan CHEN,Mengyan ZHANG,Yubao SHAO,Jian ZHOU,Xiaoyu CHEN. Effect of resveratrol mediated by the PINK1/Parkin pathway on fibroblast-like synovial cells of osteoarthritis treated with H₂O₂ [J]. The Journal of Practical Medicine, 2026, 42(3): 363-370.
[2]	Ziqing WANG,Ning DING,Lianpeng YANG,Linyun WANG,Jingrui LI,Yibin WANG,Guizhong LI,Yideng JIANG,Guanjun LU. The role of circ_0001126 in Hcy-induced ferroptosis of MPC-5 cells [J]. The Journal of Practical Medicine, 2026, 42(2): 201-211.
[3]	Abudimijiti XIEYIDAI,Xiangxin SONG,Aizezi DILIREBA,Yibulaiyin HASIYETI. Research on the correlation between specific indicators of serum ferroptosis and Alzheimer′s disease [J]. The Journal of Practical Medicine, 2026, 42(1): 94-100.
[4]	Jinshan YANG,Benzhong JIA,Siwen ZHONG,Tao LI,Dengbao. LI. Effect of lactobacillus plantarum LB12 on renal calcium oxalate stones in rats [J]. The Journal of Practical Medicine, 2025, 41(8): 1130-1138.
[5]	Yujia LU,Keying OU,Yueyang MA,Chuansu YUAN,Bin LIU,Yongfeng YANG,Qingfang. XIONG. Study on the relationship between UGT1A1 polymorphism and UGT1A1 inhibitory drugs⁃induced liver injury [J]. The Journal of Practical Medicine, 2025, 41(4): 588-593.
[6]	Junjie ZHAI,Shaoying WEN,Xinru LI,Rui SUN,Ning QI,Qifan ZHANG,Li YANG,Hui HUANG,Lingju MA,Yinju HAO,Yideng JIANG,Guizhong LI,Shengchao. MA. Role of Toll⁃like receptor 4 in regulation of homocysteine⁃induced ferroptosis in macrophages [J]. The Journal of Practical Medicine, 2025, 41(3): 313-321.
[7]	Lu ZHENG,Haohao ZHANG,Feifei WU,Jiaqi GUO,Youqin WANG,Ruimin HAO,Lihui FENG,Yan. LI. Protective effect of exenatide on oxidative stress in hypothalamus of diabetes mice and its mechanism [J]. The Journal of Practical Medicine, 2025, 41(3): 330-338.
[8]	Zhiyi CHEN,Sirui LIU,Jingxian HAN,Xuezhu. ZHANG. Interaction between DNA methylation and oxidative stress in Alzheimer′s disease： Bidirectional regulation and positive⁃feedback networks [J]. The Journal of Practical Medicine, 2025, 41(24): 3802-3808.
[9]	Haiyan LI,Mengzhu LI,Mengxuan CHEN,Da GAO,Kexin DUAN,Lijun ZHAO,Meiling ZHU. The comparison of ferroptosis characteristics and motor deficits in Parkinson′s disease mouse models [J]. The Journal of Practical Medicine, 2025, 41(22): 3501-3509.
[10]	Chengcheng LI,Anli LI,Yuhong LIU,Lu WANG,Hong PENG,Hong LI. MCT1⁃mediated lactic acid accumulation and ferroptosis in acute liver failure： A positive feedback loop [J]. The Journal of Practical Medicine, 2025, 41(22): 3520-3528.
[11]	Shaochu CHEN,Ming GONG,Wang ZHANG,Jiawen WU,Guangxin HUANG,Yadong ZHANG. Effects of exosomes secreted from mesenchymal stem cells on chondrocyte injury under hypoxia [J]. The Journal of Practical Medicine, 2025, 41(22): 3529-3536.
[12]	Xingwei WU,Jianying WANG,Chengxiao GUO,Ziyi LIU,Chao SUN,Fei. YU. The effect of remimazolam on modulating the ROS/RAGE/NF-κB signaling pathway in LPS-induced microglial inflammation [J]. The Journal of Practical Medicine, 2025, 41(2): 153-161.
[13]	Jinyan GUO,Yuqing YOU,Ke CHEN,Fen PAN,Jiahui LAI,Sufang CHEN,Weifeng. YAO. Protective mechanism of sevoflurane on acute lung injury in sepsis by regulating the Wnt/β-catenin signaling pathway [J]. The Journal of Practical Medicine, 2025, 41(19): 2991-2999.
[14]	Wenli YANG,Tong BAO,Xin LIN,Ruge NIU,Zhongchi XU,Yunhe ZHAO. Prevention and treatment of acute radiation⁃induced myocardial injury by the preparation of Abelmoschus manihot （L.） Medik （Jiahua Tablet） [J]. The Journal of Practical Medicine, 2025, 41(17): 2631-2636.
[15]	Yuancheng LI,Li. LI. Androgen‑mediated DGAT2 upregulation promotes ferroptosis in granulosa cells in polycystic ovary syndrome [J]. The Journal of Practical Medicine, 2025, 41(16): 2498-2506.