Shenqi Xiezhuo Decoction alleviates renal fibrosis in rats by ameliorating oxidative stress and inflammation through the Rap1/MAPK/FoxO3a signaling pathway

doi:10.12122/j.issn.1673-4254.2025.12.06

Abstract

Abstract:

Objective To explore the mechanism of Shenqi Xiezhuo Decoction (SQXZD) for improving renal fibrosis (RF) in rats. Methods The chemical components of SQXZD were identified using UPLC-Q Exactive/MS, and component-disease target network and enrichment analyses were conducted to screen the key pathways and targets. In the animal experiment, 49 male SD rats were randomized equally into blank control group, sham operation group, unilateral ureteral obstruction-induced RF model group, losartan treatment (daily dose 4.6 mg/kg) group, and low-, medium-, and high-dose SQXZD (9.7, 19.4, and 38.8 g/kg, respectively) treatment groups. After 14 days' treatment, renal pathologies and collagen deposition of the rats were examined with HE and Masson staining, and serum levels of BUN, Cr, SOD, MDA, GSH-px, IL-6, and TNF-α were detected. Western blotting and qRT-PCR were used to detect renal protein and mRNA expressions of α‑SMA, Col-I, NAKED2, Rap1, B-raf, Raf-1, MEK3/6, p38MAPK, MEK, ERK1/2, p-ERK1/2, FoxO3a, p-FoxO3a, and MnSOD. Results A total of 263 chemical components were identified in SQXZD. Network pharmacology revealed 170 intersecting targets between the components and RF enriched in the MAPK, Rap1, and FoxO pathways. The rat models of RF showed abnormal renal structural changes, increased fibrosis area, elevated serum BUN, Cr, MDA, IL-6, and TNF-α levels, reduced SOD and GSH-px levels, upregulated renal expressions of α‑SMA, Col-I, NAKED2, Rap1, B-raf, MEK, ERK1/2, p-ERK1/2, MEK3/6, and p38MAPK, and downregulated Raf-1, FoxO3a, p-FoxO3a, and MnSOD expressions. Treatment with losartan and SQXZD (especially at the medium dose) obviously lessened renal pathologies, improved renal functions, alleviated oxidative stress and inflammation, and ameliorated abnormal changes in the Rap1/MAPK/FoxO3a signaling pathway in the rat models. Conclusion SQXZD alleviates RF and improves renal function in rats possibly by ameliorating renal oxidative stress and inflammation via regulating the Rap1/MAPK/FoxO3a signaling pathway.

Key words: Shenqi Xiezhuo Decoction, renal fibrosis, oxidative stress, inflammatory factors, Rap1/MAPK/FoxO3a signaling pathway

Xiaoyu LU, Zhihui LIU, Ye LIU, Tianxiao PANG, Rong BIAN, Ling GUO, Xuehong HE. Shenqi Xiezhuo Decoction alleviates renal fibrosis in rats by ameliorating oxidative stress and inflammation through the Rap1/MAPK/FoxO3a signaling pathway[J]. Journal of Southern Medical University, 2025, 45(12): 2585-2597.

Figures/Tables 17

Tab.1 Chromatographic gradient

Time (min)	Aqueous phase proportion(%)	Organic phase proportion(%)
1	98	2
5	80	20
10	50	50
15	20	80
20	5	95
27	5	95
28	98	2
30	98	2

Tab.2 Primer sequences

Gene	Primer sequences (5'-3')	Fragment length (bp)
α-SMA	F:ACCATCGGGAATGAACGCTT	191
α-SMA	R:CTGTCAGCAATGCCTGGGTA	191
Col1a1	F:CGTGGAAACCTGATGTATGCTTG	169
Col1a1	R:CCTATGACTTCTGCGTCTGGTGA	169
NAKED2	F:CGCCTCTGTCAATCATTCCTC	205
NAKED2	R:ATCTGTGTTGGGCTTCCTGCTATA	205
Rap1	F:GGATTGAAGGCACCAACCAT	144
Rap1	R:AGTAATTGAAGTGCTCCTTGCCG	144
Raf-1	F:GATGCTGTCTACTCGGATTGGC	116
Raf-1	R:GAAGTTGCTCTGGAGTTGGGTC	116
B-raf	F:CGCAAGATGTGGTGTAACGG	201
B-raf	R:AAGTTGTGGGTTGTCAGAGGAA	201
MEK	F:CGTGATGTCAAACCCTCCAAC	135
MEK	R:AGGAGCCATATAGGCAGCACAG	135
MEK3	F:TGAAGATGTGCGACTTTGGC	141
MEK3	R:CATCAGACTTGACGTTGTAGCCC	141
p38MAPK	F:ACCACGACCCTGATGATGAGC	94
p38MAPK	R:TAGGTCAGGCTCTTCCATTCGT	94
ERK	F:GAGACATCCTCAGAGCACCCA	216
ERK	R:TGTTGATAAGCAGATTGGAGGG	216
Foxo3a	F:AACAGTACCGTGTTCGGACC	119
Foxo3a	R:AGTGTCTGGTTGCCGTAGTG	119
MnSOD	F:TCTGGACAAACCTGAGCCCTAA	133
MnSOD	R:GAACCTTGGACTCCCACAGACA	133
GAPDH	F:CTGGAGAAACCTGCCAAGTATG	138
GAPDH	R:GGTGGAAGAATGGGAGTTGCT	138

Fig.1 Total ion chromatogram of Shenqi Xiezhuo Decoction (SQXZD) extract (Top: positive ion mode; Bottom: negative ion mode).

Fig.2 Venn diagram of the targets of SQXZD for delaying RF.

Fig.3 "Component-Target-Disease" network diagram. Diamonds represent active components, and rectangles represent disease targets with a total of 1475 nodes and 11 241 edges.

Fig.4 PPI network diagram of the targets of SQXZD for delaying RF. Node color intensity corresponds to the Degree value, and darker colors indicate higher Degree values (169 nodes and 3682 edges).

Fig.5 GO functional enrichment analysis of SQXZD in delaying RF. BP: Biological process; CC: Cellular component; MF: Molecular function.

Fig.6 KEGG pathway enrichment analysis of SQXZD in delaying RF.

Tab.3 Effects of SQXZD on serum BUN and Cr levels in rats with unilateral ureteral obstruction (UUO) (Mean±SD, n=5)

Group	BUN (mmol/L)	Cr (μmol/L)
Control	4.94±0.29	47.48±2.62
Sham	7.18±0.32	55.48±1.10
Model	28.08±2.35**	196.11±12.88**
Losartan	18.97±1.01^#	166.99±4.07^#
SQXZD low-dose	23.49±1.09	178.97±6.42
SQXZD medium-dose	16.79±0.55^▲	149.92±2.57^▲
SQXZD high-dose	19.03±1.01^#	171.32±3.68^#

Fig.7 HE staining of the surgical-side kidney in each group of the rats (Original magnification: ×400).

Fig.8 Masson staining of the surgical-side kidney in each group of rats (×400).

Tab.4 Effects of SQXZD on serum SOD， MDA and GSH-px levels in UUO rats (Mean±SD, n=5)

Group	SOD (U/mL)	MDA (μmol/L)	GSH-px (U/mL)
Control	325.42±6.59	2.03±0.14	2582.35±54.22
Sham	257.27±16.71	2.36±0.05	2238.14±105.60
Model	87.01±2.08**	8.92±0.94**	668.21±6.81**
Losartan	212.38±5.19^#	4.26±0.38^#	2048.18±45.04^#
SQXZD low-dose	183.70±5.04^#	7.50±0.52	1516.04±66.02^#
SQXZD medium-dose	270.46±5.87^▲	2.90±0.11^▲	2218.58±51.31^▲
SQXZD high-dose	209.35±5.60^#	5.42±0.20^#	1684.99±52.96^#

Tab.5 Effects of SQXZD on serum IL-6 and TNF‑α levels in UUO rats (Mean±SD, n=5)

Group	IL-6	TNF-α
Control	0.159±0.001	0.038±0.0003
Sham	0.177±0.005	0.040±0.0004
Model	0.309±0.010**	0.056±0.0011**
Losartan	0.243±0.004^#	0.051±0.0004^#
SQXZD low-dose	0.273±0.006	0.053±0.0006
SQXZD medium-dose	0.228±0.002^▲	0.049±0.0003^▲
SQXZD high-dose	0.252±0.005^#	0.051±0.0005^#

Fig.9 Effects of SQXZD on expressions of α-SMA, Col-I and NAKED2 in the surgical-side kidneys of UUO rats. **P<0.01 vs Sham group; ##P<0.01, #P<0.05 vs Model group.

Fig.10 Effects of SQXZD on mRNA transcription levels of α-SMA, Col1a1 and NAKED2 in the surgical-side kidneys of UUO rats. **P<0.01 vs Sham group; ##P<0.01, #P<0.05 vs Model group.

Fig.11 Effects of SQXZD on expressions of Rap1, B-raf, Raf-1, MEK3/6, p38MAPK, MEK, ERK1/2, p-ERK1/2, FoxO3a, p-FoxO3a and MnSOD in surgical-side kidneys of UUO rats. **P<0.01 vs Sham group; ##P<0.01, #P<0.05 vs Model group.

Fig.12 Effects of SQXZD on mRNA transcription levels of Rap1, B-raf, Raf-1, MEK3, p38MAPK, MEK, ERK, FoxO3a and MnSOD in surgical-side kidneys of UUO rats.**P<0.01 vs Sham group; ##P<0.01, #P<0.05 vs Model group.

References 67

[1]	Liu Y. Cellular and molecular mechanisms of renal fibrosis[J]. Nat Rev Nephrol, 2011, 7(12): 684-96. doi：10.1038/nrneph.2011.149
[2]	Conway B, Hughes J. Cellular orchestrators of renal fibrosis[J]. Qjm, 2012, 105(7): 611-5. doi：10.1093/qjmed/hcr235
[3]	Zeisberg M, Neilson EG. Mechanisms of tubulointerstitial fibrosis[J]. J Am Soc Nephrol, 2010, 21(11): 1819-34. doi：10.1681/asn.2010080793
[4]	卞帅博, 张亮, 杨璇. 1990~2021年中国慢性肾脏病疾病负担变化趋势及发病预测分析[J].实用临床医药杂志, 2025, 29(6): 89-93, 98.
[5]	Kramann R, DiRocco DP, Maarouf OH, et al. Matrix-producing cells in chronic kidney disease: origin, regulation, and activation[J]. Curr Pathobiol Rep, 2013, 1(4): 301-11. doi：10.1007/s40139-013-0026-7
[6]	Su H, Wan C, Song A, et al. Oxidative stress and renal fibrosis: mechanisms and therapies[J]. Adv Exp Med Biol, 2019, 1165: 585-604. doi：10.1007/978-981-13-8871-2_29
[7]	Papaconstantinou J. The role of signaling pathways of inflammation and oxidative stress in development of senescence and aging phenotypes in cardiovascular disease[J]. Cells, 2019, 8(11): E1383. doi：10.3390/cells8111383
[8]	Kao MP, Ang DS, Pall A, et al. Oxidative stress in renal dysfunction: mechanisms, clinical sequelae and therapeutic options[J]. J Hum Hypertens, 2010, 24(1): 1-8. doi：10.1038/jhh.2009.70
[9]	Davì G, Guagnano MT, Ciabattoni G, et al. Platelet activation in obese women: role of inflammation and oxidant stress[J]. JAMA, 2002, 288(16): 2008-14. doi：10.1001/jama.288.16.2008
[10]	Duni A, Liakopoulos V, Roumeliotis S, et al. Oxidative stress in the pathogenesis and evolution of chronic kidney disease: untangling Ariadne's thread[J]. Int J Mol Sci, 2019, 20(15): E3711. doi：10.3390/ijms20153711
[11]	Lee OYA, Wong ANN, Ho CY, et al. Potentials of natural antioxidants in reducing inflammation and oxidative stress in chronic kidney disease[J]. Antioxidants: Basel, 2024, 13(6): 751. doi：10.3390/antiox13060751
[12]	梁亮.何学红教授学术思想总结及肾衰方治疗慢性肾脏病的临床与实验研究[D]. 辽宁中医药大学, 2015.
[13]	ConsortiumUniProt. UniProt: the universal protein knowledgebase in 2023[J]. Nucleic Acids Res, 2023, 51(d1): D523-31.
[14]	Amberger JS, Hamosh A. Searching online mendelian inheritance in man (OMIM): a knowledgebase of human genes and genetic phenotypes[J]. Curr Protoc Bioinformatics, 2017, 58: 1.2.1-1.2.12. doi：10.1002/cpbi.27
[15]	Stelzer G, Rosen N, Plaschkes I, et al. The GeneCards suite: from gene data mining to disease genome sequence analyses[J]. Curr Protoc Bioinformatics, 2016, 54: 1.30.1-1.30.33. doi：10.1002/cpbi.5
[16]	Piñero J, Ramírez-Anguita JM, Saüch-Pitarch J, et al. The DisGeNET knowledge platform for disease genomics: 2019 update[J]. Nucleic Acids Res, 2020, 48(d1): D845-55.
[17]	Szklarczyk D, Kirsch R, Koutrouli M, et al. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest[J]. Nucleic Acids Res, 2023, 51(d1): D638-46. doi：10.1093/nar/gkac1000
[18]	Sherman BT, Hao M, Qiu J, et al. DAVID a web server for functional enrichment analysis and functional annotation of gene lists (2021 update)[J]. Nucleic Acids Res, 2022, 50(w1): W216-21. doi：10.1093/nar/gkac194
[19]	Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules[J]. Sci Rep, 2017, 7: 42717. doi：10.1038/srep42717
[20]	Daina A, Michielin O, Zoete V. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules[J]. Nucleic Acids Res, 2019, 47(w1): W357-64. doi：10.1093/nar/gkz382
[21]	马园园, 刘成海, 陶艳艳. 肾纤维化动物模型特点与研究进展[J]. 中国实验动物学报, 2018, 26(3): 398-403.
[22]	李建省, 王英明, 闫燕顺, 等. “肾虚络瘀，肾络癥瘕”病机观与肾间质纤维化中自噬不足的相关性[J]. 中国实验方剂学杂志, 2023, 29(2):186-94.
[23]	Li W, Zhang Y, Wang Q, et al. 6-Gingerol ameliorates ulcerative colitis by inhibiting ferroptosis based on the integrative analysis of plasma metabolomics and network pharmacology[J]. Food Funct, 2024, 15(11): 6054-67. doi：10.1039/d4fo00952e
[24]	邓婷, 傅强, 李志樑, 等. 6-姜酚对心肾综合征大鼠心肾功能的影响[J]. 实用医学杂志, 2025, 41(11): 1627-36.
[25]	Wadekar PP, Salunkhe VR. Formulation and evaluation of nanobiotherapeutics of Terminalia arjuna through plant tissue culture for atherosclerosis[J]. Future J Pharm Sci, 2024, 10(1): 42. doi：10.1186/s43094-024-00613-5
[26]	Nie R, Yuan Z, Wu Y, et al. Time-dose response and mechanistic specificity of berberine in renal fibrosis from a multi-model integration perspective: a systematic review and meta-analysis on animal models[J]. Front Pharmacol, 2025, 16: 1600408. doi：10.3389/fphar.2025.1600408
[27]	陈章平, 李信晓, 郭胜楠, 等. GABRG2基因敲除小鼠和HT22细胞通过激活PKA/NF-κB信号通路影响MMP3的表达[J].宁夏医科大学学报, 2022, 44(7): 656-62.
[28]	刘星辰, 王璟, 刘博阳, 等. PTH缺失通过诱导肾脏细胞衰老和衰老相关分泌表型分子表达而加速肾脏纤维化[J]. 现代生物医学进展,2024, 24(16): 3006-12.
[29]	Agrud A, Subburaju S, Goel P, et al. Gabrb3 endothelial cell-specific knockout mice display abnormal blood flow, hypertension, and behavioral dysfunction[J]. Sci Rep, 2022, 12(1): 4922. doi：10.1038/s41598-022-08806-9
[30]	秦一冰, 吕静, 战丽彬, 等. 基于“脉络-血管系统”理论探讨肾纤维化的发病机制[J]. 世界中西医结合杂志, 2024, 19(6): 1256-9, 1264.
[31]	张晓珣, 王俊, 赵宇, 等. 牛蒡子苷元对四氯化碳致大鼠肝纤维化的治疗作用[J]. 中国药理学与毒理学杂志, 2016, 30(1): 53-60.
[32]	García-Llorca A, Carta F, Supuran CT, et al. Carbonic anhydrase, its inhibitors and vascular function[J]. Front Mol Biosci, 2024, 11: 1338528. doi：10.3389/fmolb.2024.1338528
[33]	Krishnan D, Liu L, Wiebe SA, et al. Carbonic anhydrase II binds to and increases the activity of the epithelial sodium-proton exchanger, NHE3[J]. Am J Physiol Renal Physiol, 2015, 309(4): F383-92. doi：10.1152/ajprenal.00464.2014
[34]	Fang Z, Wang Q, Duan H, et al. 17β-Estradiol mediates TGFBR3/Smad2/3 signaling to attenuate the fibrosis of TGF‑β1-induced bovine endometrial epithelial cells via GPER[J]. J Cell Physiol, 2024, 239(1): 166-79. doi：10.1002/jcp.31153
[35]	Garrington TP, Johnson GL. Organization and regulation of mitogen-activated protein kinase signaling pathways[J]. Curr Opin Cell Biol, 1999, 11(2): 211-8. doi：10.1016/s0955-0674(99)80028-3
[36]	Akhtar S, Al-Zaid B, El-Hashim AZ, et al. Impact of PAMAM delivery systems on signal transduction pathways in vivo: Modulation of ERK1/2 and p38 MAP kinase signaling in the normal and diabetic kidney[J]. Int J Pharm, 2016, 514(2): 353-63. doi：10.1016/j.ijpharm.2016.03.039
[37]	Cheng X, Gao W, Dang Y, et al. Both ERK/MAPK and TGF-Beta/Smad signaling pathways play a role in the kidney fibrosis of diabetic mice accelerated by blood glucose fluctuation[J]. J Diabetes Res, 2013, 2013: 463740. doi：10.1155/2013/463740
[38]	Wei X, Wang J, Deng YY, et al. Tubiechong patching promotes Tibia fracture healing in rats by regulating angiogenesis through the VEGF/ERK1/2 signaling pathway[J]. J Ethnopharmacol, 2023, 301: 115851. doi：10.1016/j.jep.2022.115851
[39]	Wu Y, Wang L, Deng D, et al. Renalase protects against renal fibrosis by inhibiting the activation of the ERK signaling pathways[J]. Int J Mol Sci, 2017, 18(5): E855. doi：10.3390/ijms18050855
[40]	Enslen H, Raingeaud J, Davis RJ. Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6[J]. J Biol Chem, 1998, 273(3): 1741-8. doi：10.1074/jbc.273.3.1741
[41]	Wagner EF, Nebreda AR. Signal integration by JNK and p38 MAPK pathways in cancer development[J]. Nat Rev Cancer, 2009, 9(8): 537-49. doi：10.1038/nrc2694
[42]	阮颖新, 刘素雁, 李春媚, 等. p38MAPK通路参与肾间质纤维化的实验研究[J]. 临床泌尿外科杂志, 2007, (1): 63-6.
[43]	霍振霞, 王保兴. p38MAPK在氧化应激诱导肾间质纤维化中的研究进展[J]. 中华临床医师杂志(电子版), 2016, 10(7): 1029-32.
[44]	Sari-Ak D, Torres-Gomez A, Yazicioglu YF, et al. Structural, biochemical, and functional properties of the Rap1-interacting adaptor molecule (RIAM)[J]. Biomed J, 2022, 45(2): 289-98. doi：10.1016/j.bj.2021.09.005
[45]	Mochizuki N, Yamashita S, Kurokawa K, et al. Spatio-temporal images of growth-factor-induced activation of Ras and Rap1[J]. Nature, 2001, 411(6841): 1065-8. doi：10.1038/35082594
[46]	朱雪婧. Rap1b对糖尿病肾病肾小管上皮细胞氧化损伤及凋亡的影响与机制研究[D]. 中南大学, 2011.
[47]	Kops GJ, Dansen TB, Polderman PE, et al. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress[J]. Nature, 2002, 419(6904): 316-21. doi：10.1038/nature01036
[48]	李安琪, 祝晓梅, 黄九九, 等. 乳源六肽通过FoxO3a-MnSOD通路减少酒精诱导的氧化应激缓解肝损伤[J]. 安徽医科大学学报, 2022, 57(12): 1864-9.
[49]	龚武清, 彭书生, 杜海林. 基于TNF-α/PI3K-Akt/NF-κB信号通路研究瑞舒伐他汀介导MCP-1对深静脉血栓大鼠模型凝血功能、炎症因子及纤溶指标的影响[J]. 中国老年学杂志, 2025, 45(13): 3272-6.
[50]	李玮怡, 江露, 张宗星, 等. 强骨康疏方通过抑制HIF-1α/BNIP3自噬信号通路减少类风湿性关节炎大鼠的破骨细胞分化[J]. 南方医科大学学报, 2025, 45(7): 1389-96.
[51]	Theocharis AD, Skandalis SS, Gialeli C, et al. Extracellular matrix structure[J]. Adv Drug Deliv Rev, 2016, 97: 4-27. doi：10.1016/j.addr.2015.11.001
[52]	Lv W, Booz GW, Fan F, et al. Oxidative stress and renal fibrosis: recent insights for the development of novel therapeutic strategies[J]. Front Physiol, 2018, 9: 105. doi：10.3389/fphys.2018.00105
[53]	Kuppe C, Ibrahim MM, Kranz J, et al. Decoding myofibroblast origins in human kidney fibrosis[J]. Nature, 2021, 589(7841): 281-6. doi：10.1038/s41586-020-2941-1
[54]	Genovese F, Manresa AA, Leeming DJ, et al. The extracellular matrix in the kidney: a source of novel non-invasive biomarkers of kidney fibrosis[J]? Fibrogenesis Tissue Repair, 2014, 7(1): 4. doi：10.1186/1755-1536-7-4
[55]	Sharma AK, Mauer SM, Kim Y, et al. Interstitial fibrosis in obstructive nephropathy[J]. Kidney Int, 1993, 44(4): 774-88. doi：10.1038/ki.1993.312
[56]	Locatelli F, Canaud B, Eckardt KU, et al. Oxidative stress in end-stage renal disease: an emerging threat to patient outcome[J]. Nephrol Dial Transplant, 2003, 18(7): 1272-80. doi：10.1093/ndt/gfg074
[57]	Fassett RG, Robertson IK, Ball MJ, et al. Effects of atorvastatin on oxidative stress in chronic kidney disease[J]. Nephrology: Carlton, 2015, 20(10): 697-705. doi：10.1111/nep.12502
[58]	Zachara BA. Chapter five selenium and selenium-dependent antioxidants in chronic kidney disease[J]. Adv Clin Chem, 2015, 68: 131-51. doi：10.1016/bs.acc.2014.11.006
[59]	Tsikas D. Assessment of lipid peroxidation by measuring malon-dialdehyde (MDA) and relatives in biological samples: Analytical and biological challenges[J]. Anal Biochem, 2017, 524: 13-30. doi：10.1016/j.ab.2016.10.021
[60]	Su H, Lei CT, Zhang C. Interleukin-6 signaling pathway and its role in kidney disease: an update[J]. Front Immunol, 2017, 8: 405. doi：10.3389/fimmu.2017.00405
[61]	Meldrum KK, Misseri R, Metcalfe P, et al. TNF-alpha neutralization ameliorates obstruction-induced renal fibrosis and dysfunction[J]. Am J Physiol Regul Integr Comp Physiol, 2007, 292(4): R1456-64. doi：10.1152/ajpregu.00620.2005
[62]	Wittchen ES, Worthylake RA, Kelly P, et al. Rap1 GTPase inhibits leukocyte transmigration by promoting endothelial barrier function[J]. J Biol Chem, 2005, 280(12): 11675-82. doi：10.1074/jbc.m412595200
[63]	吴华英, 邓凯, 李静, 等. 益气活血方调控cAMP/Epac1/Rap1信号改善冠心病气虚血瘀证大鼠的验证[J]. 中国实验方剂学杂志, 2024,30(18): 107-16.
[64]	沈鑫蕾, 朱清如, 余文凯, 等. 盐炙车前子调控肾小管上皮-间充质转化改善肾纤维化的机制研究[J].中国中药杂志, 2025, 50(5):1195-208.
[65]	郭锦晨. 健脾化湿清热通络法改善类风湿关节炎患者SOD的数据挖掘研究及对AMPK-FoxO3a-MnSOD信号通路的影响[D]. 安徽中医药大学, 2018.
[66]	孙荣嵘, 冯小华, 王婷婷, 等. AKT/FoxO3a通路在白藜芦醇抑制大鼠肾脏间质纤维化中的作用[J]. 药物评价研究, 2019, 42(11):2165-8.
[67]	杨伟源, 李理, 郑林鑫, 等. EGFR/Foxo3a/Snail1通路在博来霉素肺纤维化小鼠中的作用机制探讨[J]. 中国呼吸与危重监护杂志, 2020,19(4): 371-8.