Association between serum CTRP9 levels and ischemic stroke: a meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

ZHU Ziyi ¹ , NIU Qingsheng ^1,2,3 ,  JIANG Yaowen ^2,3

1. West China School of Medicine, Sichuan University, Chengdu 610041, P. R. China;
2. Department of Emergency Medicine, West China School of Medicine, Sichuan University, Chengdu 610041, P. R. China;
3. Laboratory of Emergency Medicine, Disaster Medical Center, West China Hospital of Sichuan University, Chengdu 610041, P. R. China;

Corresponding?author：

JIANG Yaowen, Email: jywfx45613739@163.com

Keywords：

C1q/TNF-related protein 9 (CTRP9); Ischemic stroke; Meta-analysis

DOI：

10.7507/1672-2531.202506044

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To systematically review the relationship between circulating C1q/TNF-related protein 9 (CTRP9) levels and ischemic stroke (IS). Methods The PubMed, Web of Science, Embase, Cochrane Library, CNKI, WanFang Data, VIP databases were electronically searched to collect studies related to the objectives from database inception to February 2025. Two reviewers independently screened the literature, extracted data, and assessed the risk of bias of the included studies. Meta-analysis was then performed using RevMan 5.3 software and Stata 15.1 software. Results A total of 13 studies were included, and the meta-analysis results showed that the serum CTRP9 level in IS patients was significantly lower than that in non IS group (P<0.001). The results of subgroup analysis suggested that TG, LDL, and CTRP3 levels may be the source of heterogeneity, while the basic characteristics of the studies (publication year, average age of patients, BMI, research area, and unit of CTRP9) and the degree of carotid atherosclerosis were not the influencing factors of heterogeneity. Conclusion The meta-analysis confirms that serum CTRP9 level in IS patients is significantly lower than that in patients without IS. The association may be modified by TG, LDL, and CTRP3 levels. Due to the limited quantity and quality of the included studies, more high-quality studies are needed to verify the above conclusion.

Citation： ZHU Ziyi, NIU Qingsheng, JIANG Yaowen. Association between serum CTRP9 levels and ischemic stroke: a meta-analysis. Chinese Journal of Evidence-Based Medicine, 2026, 26(3): 314-319. doi: 10.7507/1672-2531.202506044 Copy

1.	申青仙, 張賽, 涂悅, 等. 急性缺血性腦卒中的臨床治療研究進展. 中國醫藥, 2020, 15(4): 633-636.
2.	Asada M, Morioka T, Yamazaki Y, et al. Plasma C1q/TNF-related protein-9 levels are associated with atherosclerosis in patients with type 2 diabetes without renal dysfunction. J Diabetes Res, 2016, 2016: 8624313.
3.	Uemura Y, Shibata R, Ohashi K, et al. Adipose-derived factor CTRP9 attenuates vascular smooth muscle cell proliferation and neointimal formation. FASEB J, 2013, 27(1): 25-33.
4.	Wang X, Ma X, Zeng Y, et al. Hypermethylation of the CTRP9 promoter region promotes Hcy induced VSMC lipid deposition and foam cell formation via negatively regulating ER stress. Sci Rep, 2023, 13(1): 19438.
5.	Dávila-Román VG, Barzilai B, Wareing TH, et al. Atherosclerosis of the ascending aorta. Prevalence and role as an independent predictor of cerebrovascular events in cardiac patients. Stroke, 1994, 25(10): 2010-2016.
6.	Zhu Z, Niu Q, Tang S, et al. Association between circulating CTRP9 levels and coronary artery disease: a systematic review and meta-analysis. PeerJ, 2024, 12: e18488.
7.	Yang C, Fan F, Sawmiller D, et al. C1q/TNF-related protein 9: a novel therapeutic target in ischemic stroke. J Neurosci Res, 2019, 97(2): 128-136.
8.	羅德惠, 萬翔, 劉際明, 等. 如何實現從樣本量、中位數、極值或四分位數到均數與標準差的轉換. 中國循證醫學雜志, 2017, 17(11): 1350-1356.
9.	Wells G, Shea B, O'connell D, et al. The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Canada: Ottawa Hospital Research Institute, 2014.
10.	王勝, 趙佳源, 許煜恒, 等. 血清PDGF、CTRP9、SIRT1水平與急性腦梗死患者病情的相關性及臨床意義. 中國血液流變學雜志, 2024, 34(2): 218-221, 236.
11.	戴建立, 李榕, 劉海婷, 等. 腦梗死患者血清CTRP9水平的改變及其臨床意義. 中華內科雜志, 2019, 58(6): 449-452.
12.	林翔東, 邵愛民. ACI患者血清CTRP9APN水平與頸動脈粥樣硬化的相關性分析. 浙江臨床醫學, 2015, 17(1): 93-95.
13.	劉宏娜, 李曉宇, 宋愛霞, 等. 急性腦梗死患者血清CTRP3及CTRP9水平與頸總動脈內膜中層厚度的相關性分析. 臨床和實驗醫學雜志, 2024, 23(11): 1153-1156.
14.	潘東, 段英杰. 急性缺血性腦卒中患者血清CTRP-9、NSE水平與神經功能缺損程度及卒中后認知障礙發生的關系. 山東醫藥, 2023, 63(63): 61-64.
15.	何濤, 索志超, 孔德強, 等. 術前血清CTRP3, CTRP9水平與缺血性腦卒中患者頸動脈支架成形術后再狹窄的相關性研究. 卒中與神經疾病, 2022, 29(5): 427-431.
16.	吳斌, 陳清清, 陳巨羅, 等. 補體C1q和腫瘤壞死因子相關蛋白9在缺血性腦卒中患者中的表達及意義. 中華老年心腦血管病雜志, 2022, 24(1): 59-62.
17.	張翔, 陳薪旭, 馮曉麗. 急性腦梗死患者血清CTRP3, CTRP9水平與頸總動脈內膜中層厚度的相關性分析. 卒中與神經疾病, 2021, 28(2): 162-166.
18.	何裕暢. 急性大動脈粥樣硬化型腦梗死患者血清CTRP9濃度水平及相關性分析. 衡陽: 南華大學, 2020.
19.	溫理軍, 肖步云, 張萬林. 急性腦梗死患者血清CTRP3, CTRP9水平與頸總動脈內膜中層厚度的相關性研究. 卒中與神經疾病, 2019, 26(5): 599-602.
20.	高喜斌, 高亞軍, 劉強. 血清CTRP3、CTRP9在急性腦梗死患者中的表達及診斷價值研究. 中國現代醫學雜志, 2020, 30(8): 90-93.
21.	Zhang YQ, Zhang YW, Dai JL, et al. Serum CTRP9 and high-molecular weight adiponectin are associated with ischemic stroke. BMC Neurol, 2022, 22(1): 429.
22.	Yang C, Xin JY, Liu ZL, et al. Association between serum C1q tumor necrosis factor-related protein 9 and the clinical characteristics and prognosis of ischemic stroke. Neurol Ther, 2022, 11(1): 87-101.
23.	Wolf RM, Steele KE, Peterson LA, et al. C1q/TNF-related protein-9 (CTRP9) levels are associated with obesity and decrease following weight loss surgery. J Clin Endocrinol Metab, 2016, 101(5): 2211-2217.
24.	Niu Q, Zhu Z, Jiang Y, et al. Association between circulating plasma CTRP3 levels and acute ischemic stroke: a systematic review and meta-analysis. Front Neurosci, 2025, 19: 1582743.
25.	Guo S, Mao X, Liu J. Multi-faceted roles of C1q/TNF-related proteins family in atherosclerosis. Front Immunol, 2023, 14: 1253433.
26.	Wang W, Lau WB, Wang Y, et al. Reduction of CTRP9, a novel anti-platelet adipokine, contributes to abnormal platelet activity in diabetic animals. Cardiovasc Diabetol, 2016, 15: 6.
27.	Zheng Q, Yuan Y, Yi W, et al. C1q/TNF-related proteins, a family of novel adipokines, induce vascular relaxation through the adiponectin receptor-1/AMPK/eNOS/nitric oxide signaling pathway. Arterioscler Thromb Vasc Biol, 2011, 31(11): 2616-2623.
28.	Ramiro L, Simats A, García-Berrocoso T, et al. Inflammatory molecules might become both biomarkers and therapeutic targets for stroke management. Ther Adv Neurol Disord, 2018, 11: 1756286418789340.
29.	Thundyil J, Pavlovski D, Sobey CG, et al. Adiponectin receptor signalling in the brain. Br J Pharmacol, 2012, 165(2): 313-327.
30.	Liu J, Sui H, Zhao J, et al. Osmotin protects H9c2 cells from simulated ischemia-reperfusion injury through AdipoR1/PI3K/AKT signaling pathway. Front Physiol, 2017, 8: 611.
31.	Xu N, Zhang Y, Doycheva DM, et al. Adiponectin attenuates neuronal apoptosis induced by hypoxia-ischemia via the activation of AdipoR1/APPL1/LKB1/AMPK pathway in neonatal rats. Neuropharmacology, 2018, 133: 415-428.
32.	Zhao L, Zhang JH, Sherchan P, et al. Administration of rCTRP9 attenuates neuronal apoptosis through AdipoR1/PI3K/Akt signaling pathway after ICH in mice. Cell Transplant, 2019, 28(6): 756-766.
33.	Peterson JM, Wei Z, Seldin MM, et al. CTRP9 transgenic mice are protected from diet-induced obesity and metabolic dysfunction. Am J Physiol Regul Integr Comp Physiol, 2013, 305(5): R522-533.
34.	Wei Z, Lei X, Petersen PS, et al. Targeted deletion of C1q/TNF-related protein 9 increases food intake, decreases insulin sensitivity, and promotes hepatic steatosis in mice. Am J Physiol Endocrinol Metab, 2014, 306(7): E779-E790.
35.	Manninen V, Tenkanen L, Koskinen P, et al. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment. Circulation, 1992, 85(1): 37-45.
36.	Herrero-Martín G, H?yer-Hansen M, García-García C, et al. TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells. EMBO J, 2009, 28(6): 677-685.
37.	Werstuck GH, Lentz SR, Dayal S, et al. Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. J Clin Invest, 2001, 107(10): 1263-1273.
38.	Austin MA, Breslow JL, Hennekens CH, et al. Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA, 1988, 260(13): 1917-1921.
39.	Zhang L, Liu Q, Zhang H, et al. C1q/TNF-related protein 9 inhibits THP-1 macrophage foam cell formation by enhancing autophagy. J Cardiovasc Pharmacol, 2018, 72(4): 167-175.
40.	Deng W, Li C, Zhang Y, et al. Serum C1q/TNF-related protein-3 (CTRP3) levels are decreased in obesity and hypertension and are negatively correlated with parameters of insulin resistance. Diabetol Metab Syndr, 2015, 7: 33.
41.	Gao J, Qian T, Wang W. CTRP3 activates the AMPK/SIRT1-PGC-1α pathway to protect mitochondrial biogenesis and functions in cerebral ischemic stroke. Neurochem Res, 2020, 45(12): 3045-3058.
42.	Wang S, Zhou Y, Yang B, et al. C1q/tumor necrosis factor-related protein-3 attenuates brain injury after intracerebral hemorrhage via AMPK-dependent pathway in rat. Front Cell Neurosci, 2016, 10: 237.
43.	Yang B, Wang S, Yu S, et al. C1q/tumor necrosis factor-related protein 3 inhibits oxidative stress during intracerebral hemorrhage via PKA signaling. Brain Res, 2017, 1657: 176-184.
44.	Glagov S, Weisenberg E, Zarins CK, et al. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med, 1987, 316(22): 1371-1375.
45.	Li J, Zhang P, Li T, et al. CTRP9 enhances carotid plaque stability by reducing pro-inflammatory cytokines in macrophages. Biochem Biophys Res Commun, 2015, 458(4): 890-895.
46.	Zhao L, Chen S, Sherchan P, et al. Recombinant CTRP9 administration attenuates neuroinflammation via activating adiponectin receptor 1 after intracerebral hemorrhage in mice. J Neuroinflammation, 2018, 15(1): 215.
47.	Adams HP, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke, 1993, 24(1): 35-41.
48.	Khoshnam SE, Winlow W, Farzaneh M, et al. Pathogenic mechanisms following ischemic stroke. Neurol Sci, 2017, 38(7): 1167-1186.

1. 申青仙, 張賽, 涂悅, 等. 急性缺血性腦卒中的臨床治療研究進展. 中國醫藥, 2020, 15(4): 633-636.
2. Asada M, Morioka T, Yamazaki Y, et al. Plasma C1q/TNF-related protein-9 levels are associated with atherosclerosis in patients with type 2 diabetes without renal dysfunction. J Diabetes Res, 2016, 2016: 8624313.
3. Uemura Y, Shibata R, Ohashi K, et al. Adipose-derived factor CTRP9 attenuates vascular smooth muscle cell proliferation and neointimal formation. FASEB J, 2013, 27(1): 25-33.
4. Wang X, Ma X, Zeng Y, et al. Hypermethylation of the CTRP9 promoter region promotes Hcy induced VSMC lipid deposition and foam cell formation via negatively regulating ER stress. Sci Rep, 2023, 13(1): 19438.
5. Dávila-Román VG, Barzilai B, Wareing TH, et al. Atherosclerosis of the ascending aorta. Prevalence and role as an independent predictor of cerebrovascular events in cardiac patients. Stroke, 1994, 25(10): 2010-2016.
6. Zhu Z, Niu Q, Tang S, et al. Association between circulating CTRP9 levels and coronary artery disease: a systematic review and meta-analysis. PeerJ, 2024, 12: e18488.
7. Yang C, Fan F, Sawmiller D, et al. C1q/TNF-related protein 9: a novel therapeutic target in ischemic stroke. J Neurosci Res, 2019, 97(2): 128-136.
8. 羅德惠, 萬翔, 劉際明, 等. 如何實現從樣本量、中位數、極值或四分位數到均數與標準差的轉換. 中國循證醫學雜志, 2017, 17(11): 1350-1356.
9. Wells G, Shea B, O'connell D, et al. The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Canada: Ottawa Hospital Research Institute, 2014.
10. 王勝, 趙佳源, 許煜恒, 等. 血清PDGF、CTRP9、SIRT1水平與急性腦梗死患者病情的相關性及臨床意義. 中國血液流變學雜志, 2024, 34(2): 218-221, 236.
11. 戴建立, 李榕, 劉海婷, 等. 腦梗死患者血清CTRP9水平的改變及其臨床意義. 中華內科雜志, 2019, 58(6): 449-452.
12. 林翔東, 邵愛民. ACI患者血清CTRP9APN水平與頸動脈粥樣硬化的相關性分析. 浙江臨床醫學, 2015, 17(1): 93-95.
13. 劉宏娜, 李曉宇, 宋愛霞, 等. 急性腦梗死患者血清CTRP3及CTRP9水平與頸總動脈內膜中層厚度的相關性分析. 臨床和實驗醫學雜志, 2024, 23(11): 1153-1156.
14. 潘東, 段英杰. 急性缺血性腦卒中患者血清CTRP-9、NSE水平與神經功能缺損程度及卒中后認知障礙發生的關系. 山東醫藥, 2023, 63(63): 61-64.
15. 何濤, 索志超, 孔德強, 等. 術前血清CTRP3, CTRP9水平與缺血性腦卒中患者頸動脈支架成形術后再狹窄的相關性研究. 卒中與神經疾病, 2022, 29(5): 427-431.
16. 吳斌, 陳清清, 陳巨羅, 等. 補體C1q和腫瘤壞死因子相關蛋白9在缺血性腦卒中患者中的表達及意義. 中華老年心腦血管病雜志, 2022, 24(1): 59-62.
17. 張翔, 陳薪旭, 馮曉麗. 急性腦梗死患者血清CTRP3, CTRP9水平與頸總動脈內膜中層厚度的相關性分析. 卒中與神經疾病, 2021, 28(2): 162-166.
18. 何裕暢. 急性大動脈粥樣硬化型腦梗死患者血清CTRP9濃度水平及相關性分析. 衡陽: 南華大學, 2020.
19. 溫理軍, 肖步云, 張萬林. 急性腦梗死患者血清CTRP3, CTRP9水平與頸總動脈內膜中層厚度的相關性研究. 卒中與神經疾病, 2019, 26(5): 599-602.
20. 高喜斌, 高亞軍, 劉強. 血清CTRP3、CTRP9在急性腦梗死患者中的表達及診斷價值研究. 中國現代醫學雜志, 2020, 30(8): 90-93.
21. Zhang YQ, Zhang YW, Dai JL, et al. Serum CTRP9 and high-molecular weight adiponectin are associated with ischemic stroke. BMC Neurol, 2022, 22(1): 429.
22. Yang C, Xin JY, Liu ZL, et al. Association between serum C1q tumor necrosis factor-related protein 9 and the clinical characteristics and prognosis of ischemic stroke. Neurol Ther, 2022, 11(1): 87-101.
23. Wolf RM, Steele KE, Peterson LA, et al. C1q/TNF-related protein-9 (CTRP9) levels are associated with obesity and decrease following weight loss surgery. J Clin Endocrinol Metab, 2016, 101(5): 2211-2217.
24. Niu Q, Zhu Z, Jiang Y, et al. Association between circulating plasma CTRP3 levels and acute ischemic stroke: a systematic review and meta-analysis. Front Neurosci, 2025, 19: 1582743.
25. Guo S, Mao X, Liu J. Multi-faceted roles of C1q/TNF-related proteins family in atherosclerosis. Front Immunol, 2023, 14: 1253433.
26. Wang W, Lau WB, Wang Y, et al. Reduction of CTRP9, a novel anti-platelet adipokine, contributes to abnormal platelet activity in diabetic animals. Cardiovasc Diabetol, 2016, 15: 6.
27. Zheng Q, Yuan Y, Yi W, et al. C1q/TNF-related proteins, a family of novel adipokines, induce vascular relaxation through the adiponectin receptor-1/AMPK/eNOS/nitric oxide signaling pathway. Arterioscler Thromb Vasc Biol, 2011, 31(11): 2616-2623.
28. Ramiro L, Simats A, García-Berrocoso T, et al. Inflammatory molecules might become both biomarkers and therapeutic targets for stroke management. Ther Adv Neurol Disord, 2018, 11: 1756286418789340.
29. Thundyil J, Pavlovski D, Sobey CG, et al. Adiponectin receptor signalling in the brain. Br J Pharmacol, 2012, 165(2): 313-327.
30. Liu J, Sui H, Zhao J, et al. Osmotin protects H9c2 cells from simulated ischemia-reperfusion injury through AdipoR1/PI3K/AKT signaling pathway. Front Physiol, 2017, 8: 611.
31. Xu N, Zhang Y, Doycheva DM, et al. Adiponectin attenuates neuronal apoptosis induced by hypoxia-ischemia via the activation of AdipoR1/APPL1/LKB1/AMPK pathway in neonatal rats. Neuropharmacology, 2018, 133: 415-428.
32. Zhao L, Zhang JH, Sherchan P, et al. Administration of rCTRP9 attenuates neuronal apoptosis through AdipoR1/PI3K/Akt signaling pathway after ICH in mice. Cell Transplant, 2019, 28(6): 756-766.
33. Peterson JM, Wei Z, Seldin MM, et al. CTRP9 transgenic mice are protected from diet-induced obesity and metabolic dysfunction. Am J Physiol Regul Integr Comp Physiol, 2013, 305(5): R522-533.
34. Wei Z, Lei X, Petersen PS, et al. Targeted deletion of C1q/TNF-related protein 9 increases food intake, decreases insulin sensitivity, and promotes hepatic steatosis in mice. Am J Physiol Endocrinol Metab, 2014, 306(7): E779-E790.
35. Manninen V, Tenkanen L, Koskinen P, et al. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment. Circulation, 1992, 85(1): 37-45.
36. Herrero-Martín G, H?yer-Hansen M, García-García C, et al. TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells. EMBO J, 2009, 28(6): 677-685.
37. Werstuck GH, Lentz SR, Dayal S, et al. Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. J Clin Invest, 2001, 107(10): 1263-1273.
38. Austin MA, Breslow JL, Hennekens CH, et al. Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA, 1988, 260(13): 1917-1921.
39. Zhang L, Liu Q, Zhang H, et al. C1q/TNF-related protein 9 inhibits THP-1 macrophage foam cell formation by enhancing autophagy. J Cardiovasc Pharmacol, 2018, 72(4): 167-175.
40. Deng W, Li C, Zhang Y, et al. Serum C1q/TNF-related protein-3 (CTRP3) levels are decreased in obesity and hypertension and are negatively correlated with parameters of insulin resistance. Diabetol Metab Syndr, 2015, 7: 33.
41. Gao J, Qian T, Wang W. CTRP3 activates the AMPK/SIRT1-PGC-1α pathway to protect mitochondrial biogenesis and functions in cerebral ischemic stroke. Neurochem Res, 2020, 45(12): 3045-3058.
42. Wang S, Zhou Y, Yang B, et al. C1q/tumor necrosis factor-related protein-3 attenuates brain injury after intracerebral hemorrhage via AMPK-dependent pathway in rat. Front Cell Neurosci, 2016, 10: 237.
43. Yang B, Wang S, Yu S, et al. C1q/tumor necrosis factor-related protein 3 inhibits oxidative stress during intracerebral hemorrhage via PKA signaling. Brain Res, 2017, 1657: 176-184.
44. Glagov S, Weisenberg E, Zarins CK, et al. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med, 1987, 316(22): 1371-1375.
45. Li J, Zhang P, Li T, et al. CTRP9 enhances carotid plaque stability by reducing pro-inflammatory cytokines in macrophages. Biochem Biophys Res Commun, 2015, 458(4): 890-895.
46. Zhao L, Chen S, Sherchan P, et al. Recombinant CTRP9 administration attenuates neuroinflammation via activating adiponectin receptor 1 after intracerebral hemorrhage in mice. J Neuroinflammation, 2018, 15(1): 215.
47. Adams HP, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke, 1993, 24(1): 35-41.
48. Khoshnam SE, Winlow W, Farzaneh M, et al. Pathogenic mechanisms following ischemic stroke. Neurol Sci, 2017, 38(7): 1167-1186.

Chinese Journal of Evidence-Based Medicine

Association between serum CTRP9 levels and ischemic stroke: a meta-analysis

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