Multifunctional Roles and Therapeutic Prospects of C1q/TNF-Related Protein 3 (CTRP3) in Human Diseases

Abstract

Adipokines, including C1q/tumor necrosis factor (TNF)-related proteins (CTRPs), adiponectin, TNF-α, and leptin, are crucial bioactive molecules that are secreted by adipose tissue and circulate in the bloodstream. To date, 15 members of the CTRP family, which are collectively classified as part of the C1q/TNF superfamily, have been identified. Among these, CTRP3 stands out as a unique adipokine because of its distinct structural and functional properties. Recent research has highlighted the significant role of CTRP3 in the pathogenesis of various diseases. This review aims to comprehensively summarize the involvement and mechanisms of CTRP3 in the development of numerous disorders, as well as its potential therapeutic implications.

Keywords

C1q/TNF-related protein 3 (CTRP3) / Adipokine / Metabolic disorders / Cardiovascular disease / Inflammation / Fibrosis / Therapeutic target / Bone disease / Tumor regulation / Apoptosis

References

[1] Si Y, Fan W, Sun L. A review of the relationship between ctrp family and coronary artery disease. Current atherosclerosis reports., 2020, 22(6): 22

[2] Li Y, Wright GL, Peterson JM. C1q/TNF-Related Protein 3 (CTRP3) Function and Regulation. Compr Physiol., 2017, 7(3863-878

[3] Yi W, Sun Y, Yuan Y, et al.. C1q/tumor necrosis factor-related protein-3, a newly identified adipokine, is a novel antiapoptotic, proangiogenic, and cardioprotective molecule in the ischemic mouse heart. Circulation., 2012, 125(25): 3159-3169

[4] Schmid A, Pankuweit S, Vlacil A-K, et al.. Decreased circulating CTRP3 levels in acute and chronic cardiovascular patients. J Mol Med (Berl)., 2024, 102(5): 667-677

[5] Peterson JM, Wei Z, Wong GW. C1q/TNF-related protein-3 (CTRP3), a novel adipokine that regulates hepatic glucose output. J Biol Chem., 2010, 285(51): 39691-39701

[6] Guo B, Zhuang T, Xu F, et al.. New insights into implications of CTRP3 in obesity, metabolic dysfunction, and cardiovascular diseases: potential of therapeutic interventions. Front Physiol., 2020, 11570270

[7] Zhang C-L, Wu L-L, Li L. Research progress of complement-C1q/tumor necrosis factor-related protein 3. Sheng Li Xue Bao., 2017, 69(5): 666-676

[8] Maeda T, Abe M, Kurisu K, et al.. Molecular cloning and characterization of a novel gene, CORS26, encoding a putative secretory protein and its possible involvement in skeletal development. J Biol Chem., 2001, 276(5): 3628-3634

[9] Maeda T, Jikko A, Abe M, et al.. Cartducin, a paralog of Acrp30/adiponectin, is induced during chondrogenic differentiation and promotes proliferation of chondrogenic precursors and chondrocytes. J Cell Physiol., 2006, 206(2): 537-544

[10] Wong GW, Wang J, Hug C, et al.. A family of Acrp30/adiponectin structural and functional paralogs. Proc Natl Acad Sci U S A., 2004, 101(28): 10302-10307

[11] Song Y, Zhang Y, Wan Z, et al.. CTRP3 alleviates cardiac ischemia/reperfusion injury via LAMP1/JIP2/JNK signaling pathway. Aging (Albany NY)., 2022, 14(3): 1321-1335

[12] Li Y, Ozment T, Wright GL, et al.. Identification of putative receptors for the novel adipokine CTRP3 using ligand-receptor capture technology. PloS One., 2016, 11(10e0164593

[13] Shi L, Tan Y, Zheng W, et al.. CTRP3 alleviates mitochondrial dysfunction and oxidative stress injury in pathological cardiac hypertrophy by activating UPRmt via the SIRT1/ATF5 axis. Cell Death Discovery., 2024, 10(1): 53

[14] Wolf RM, Lei X, Yang Z-C, et al.. CTRP3 deficiency reduces liver size and alters IL-6 and TGFβ levels in obese mice. Am J Physiol Endocrinol Metab., 2016, 310(5E332-E345

[15] Schmid A, Roderfeld M, Gehl J, et al. C1q/TNF-related protein 3 (CTRP-3) deficiency of adipocytes affects white adipose tissue mass but not systemic CTRP-3 concentrations. Int J Mol Sci. 2021.7;22(4):1670.

[16] Schmid A, Vlacil AK, Schuett J, et al. Anti-inflammatory effects of C1q/tumor necrosis factor-related protein 3 (CTRP3) in endothelial cells. Cells. 2021;10(8):2146.

[17] Li X, Jiang L, Yang M, et al.. Impact of weight cycling on CTRP3 expression, adipose tissue inflammation and insulin sensitivity in C57BL/6J mice. Exp Ther Med., 2018, 16(3): 2052-2059

[18] Ma Z-G, Yuan Y-P, Xu S-C, et al.. CTRP3 attenuates cardiac dysfunction, inflammation, oxidative stress and cell death in diabetic cardiomyopathy in rats. Diabetologia., 2017, 60(6): 1126-1137

[19] Zhang J, Lin X, Xu J, et al.. CTRP3 protects against uric acid-induced endothelial injury by inhibiting inflammation and oxidase stress in rats. Exp Biol Med (Maywood)., 2022, 247(2): 174-183

[20] Chen L, Qin L, Liu X, et al.. CTRP3 alleviates Ox-LDL-induced inflammatory response and endothelial dysfunction in mouse aortic endothelial cells by activating the PI3K/Akt/eNOS pathway. Inflammation., 2019, 42(4): 1350-1359

[21] Lin J, Liu Q, Zhang H, et al.. C1q/Tumor necrosis factor-related protein-3 protects macrophages against LPS-induced lipid accumulation, inflammation and phenotype transition via PPARγ and TLR4-mediated pathways. Oncotarget., 2017, 8(47): 82541-82557

[22] Nishimoto H, Yamamoto A, Furukawa S, et al.. C1q/TNF-related protein 3 expression and effects on adipocyte differentiation of 3T3-L1 cells. Cell Biol Int., 2017, 41(2): 197-203

[23] Zhu H, Ding Y, Zhang Y, et al.. CTRP3 induces an intermediate switch of CD14CD16 monocyte subset with anti-inflammatory phenotype. Exp Ther Med., 2020, 19(3): 2243-2251

[24] Kopp A, Bala M, Buechler C, et al.. C1q/TNF-related protein-3 represents a novel and endogenous lipopolysaccharide antagonist of the adipose tissue. Endocrinology., 2010, 151(11): 5267-5278

[25] Hofmann C, Chen N, Obermeier F, et al.. C1q/TNF-related protein-3 (CTRP-3) is secreted by visceral adipose tissue and exerts antiinflammatory and antifibrotic effects in primary human colonic fibroblasts. Inflamm Bowel Dis., 2011, 17(12): 2462-2471

[26] Zhang R, Zhong L, Zhou J, et al.. Complement-C1q TNF-related protein 3 alleviates mesangial cell activation and inflammatory response stimulated by secretory IgA. Am J Nephrol., 2016, 43(6): 460-468

[27] Yuan Y-P, Ma Z-G, Zhang X, et al.. CTRP3 protected against doxorubicin-induced cardiac dysfunction, inflammation and cell death via activation of Sirt1. Journal of molecular and cellular cardiology., 2018, 114: 38-47

[28] Wei W-Y, Ma Z-G, Zhang N, et al.. Overexpression of CTRP3 protects against sepsis-induced myocardial dysfunction in mice. Mol Cell Endocrinol., 2018, 476: 27-36

[29] Peterson JM, Seldin MM, Wei Z, et al.. CTRP3 attenuates diet-induced hepatic steatosis by regulating triglyceride metabolism. Am J Physiol Gastrointest Liver Physiol., 2013, 305(3): G214-G224

[30] Trogen G, Bacon J, Li Y, et al.. Transgenic overexpression of CTRP3 prevents alcohol-induced hepatic triglyceride accumulation. Am J Physiol Endocrinol Metab., 2018, 315(5): E949-E960

[31] Zhang J, He J. CTRP3 inhibits high glucose-induced oxidative stress and apoptosis in retinal pigment epithelial cells. Artif Cells Nanomed Biotechnol., 2019, 47(1): 3758-3764

[32] Meng J, Wang DM, Luo LL. CTRP3 acts as a novel regulator in depressive-like behavior associated inflammation and apoptosis by meditating p38 and JNK MAPK signaling. Biomed Pharmacother. 2019;120:109489.

[33] Hou M, Liu J, Liu F, et al. C1q tumor necrosis factor-related protein-3 protects mesenchymal stem cells against hypoxia- and serum deprivation-induced apoptosis through the phosphoinositide 3-kinase/Akt pathway. Int J Mol Med. 2014;33(1):97–104.

[34] Zhang B, Zhang P, Tan Y, et al.. C1q-TNF-related protein-3 attenuates pressure overload-induced cardiac hypertrophy by suppressing the p38/CREB pathway and p38-induced ER stress. Cell death & disease., 2019, 10(7): 520

[35] Wu D, Lei H, Wang J-Y, et al.. CTRP3 attenuates post-infarct cardiac fibrosis by targeting Smad3 activation and inhibiting myofibroblast differentiation. J Mol Med (Berl)., 2015, 93(121311-1325

[36] Liu N, Gong Z, Li Y, et al. CTRP3 inhibits myocardial fibrosis through the P2X7R-NLRP3 inflammasome pathway in SHR rats. J Hypertens. 2023;42(2):315-328.

[37] Cheng C, Yu S, Kong R, et al. CTRP3 attenuates hepatic stellate cell activation through transforming growth factor-β/Smad signaling pathway. Biomed Pharmacother. 2017;89:1387-1391.

[38] Sun BR, Li HY, Wang GP, et al.. C1q/tumor necrosis factor-related protein-3 acts as a target treating hepatic fibrosis. European review for medical and pharmacological sciences., 2021, 25(17): 5374-5382

[39] Chen X, Wu Y, Diao Z, et al.. C1q/tumor necrosis factor-related protein-3 improves renal fibrosis via inhibiting notch signaling pathways. J Cell Physiol., 2019, 234(12): 22352-22364

[40] Lin S, Ma S, Lu P, et al.. Effect of CTRP3 on activation of adventitial fibroblasts induced by TGF-β1 from rat aorta in vitro. Int J Clin Exp Pathol., 2014, 7(5): 2199-2208

[41] Ouchi N, Parker JL, Lugus JJ, et al.. Adipokines in inflammation and metabolic disease. Nat Rev Immunol., 2011, 11(2): 85-97

[42] Yang Y, Li Y, Ma Z, et al.. A brief glimpse at CTRP3 and CTRP9 in lipid metabolism and cardiovascular protection. Prog Lipid Res., 2016, 64: 170-177

[43] Jain NB, Yadav A, Shankar N, et al.. Correlation of C1q/TNF-related protein-3 with cardiac autonomic tone and metabolic parameters in obesity. Int J Endocrinol Metab., 2019, 17(2e74250

[44] 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

[45] Chen T, Wang F, Chu Z, et al.. Serum CTRP3 levels in obese children: a potential protective adipokine of obesity, insulin sensitivity and pancreatic β Cell function. Diabetes Metab Syndr Obes., 2019, 12: 1923-1930

[46] Maeda T, Wakisaka S. Deficiency of C1q/TNF-related protein 3 (CTRP3) decreases adipose tissue weight in diet-induced obesity mice. Molecular biology reports., 2020, 47(11): 9219-9224

[47] Koldemir Gündüz M. BGM, a Newly Synthesised Boron Compound, Induces Apoptosis and Reduces Oxidative Stress by Inhibiting Lipogenesis in 3T3-L1 Adipocytes via PPARγ and CTRP3. Biol Trace Elem Res. 2022.

[48] Yaribeygi H, Rashidfarrokhi F, Atkin SL, et al.. C1q/TNF-related protein-3 and glucose homeostasis. Diabetes Metab Syndr., 2019, 13(3): 1923-1927

[49] Trogen G, Alamian A, Peterson JM. High molecular weight, but not total, CTRP3 levels are associated with serum triglyceride levels. Physiol Rep., 2019, 7(23e14306

[50] Li X, Jiang L, Yang M, et al.. CTRP3 improves the insulin sensitivity of 3T3-L1 adipocytes by inhibiting inflammation and ameliorating insulin signalling transduction. Endokrynol Pol., 2014, 65(4): 252-258

[51] Li X, Jiang L, Yang M, et al.. CTRP3 modulates the expression and secretion of adipokines in 3T3-L1 adipocytes. Endocr J., 2014, 61(12): 1153-1162

[52] Yan Z, Zhao J, Gan L, et al.. CTRP3 is a novel biomarker for diabetic retinopathy and inhibits HGHL-induced VCAM-1 expression in an AMPK-dependent manner. PloS one., 2017, 12(6e0178253

[53] Zeng X, Peng Y, Wang Y, et al.. C1q/tumor necrosis factor-related protein-3 (CTRP3) activated by forkhead box O4 (FOXO4) down-regulation protects retinal pericytes against high glucose-induced oxidative damage through nuclear factor erythroid 2-related factor 2 (Nrf2)/Nuclear factor-kappaB (NF-κB) signaling. Bioengineered., 2022, 13(3): 6080-6091

[54] Yan Z, Wang C, Meng Z, et al. C1q/TNF-Related Protein 3 Prevents Diabetic Retinopathy via AMPK-Dependent Stabilization of Blood-Retinal Barrier Tight Junctions. Cells. 2022;11(5):779.

[55] Yan Z, Cao X, Wang C, et al.. C1q/tumor necrosis factor-related protein-3 improves microvascular endothelial function in diabetes through the AMPK/eNOS/NO· signaling pathway. Biochem Pharmacol., 2022, 195114745

[56] Moradi N, Fadaei R, Khamseh ME, et al.. Serum levels of CTRP3 in diabetic nephropathy and its relationship with insulin resistance and kidney function. PloS one., 2019, 14(4e0215617

[57] Du C, Zhu Y, Yang Y, et al.. C1q/tumour necrosis factor-related protein-3 alleviates high-glucose-induced lipid accumulation and necroinflammation in renal tubular cells by activating the adenosine monophosphate-activated protein kinase pathway. Int J Biochem Cell Biol., 2022, 149106247

[58] Hu TY, Li LM, Pan YZ. CTRP3 inhibits high glucose-induced human glomerular mesangial cell dysfunction. J Cell Biochem., 2019, 120(4): 5729-5736

[59] Du C, Zhu Y, Yang Y, et al. C1q/tumour necrosis factor-related protein-3 alleviates high-glucose-induced lipid accumulation and necroinflammation in renal tubular cells by activating the adenosine monophosphate-activated protein kinase pathway. Int J Biochem Cell Biol. 2022:106247.

[60] Song Y, Mai H, Lin Y, et al.. MiR-144 affects proliferation and apoptosis of high glucose-induced AC16 cardiomyocytes by regulating CTRP3/JNK signaling. International journal of clinical and experimental pathology., 2020, 13(2): 142-152

[61] Zhou W, Wang Y, Wu Y, et al. Serum CTRP3 level is inversely associated with nonalcoholic fatty liver disease: A 3-y longitudinal study. Clin Chim Acta. 2018;479:79–83.

[62] Elseweidy MM, Elesawy AE, Sobh MS, et al.. Ellagic acid ameliorates high fructose-induced hyperuricemia and non-alcoholic fatty liver in Wistar rats: Focusing on the role of C1q/tumor necrosis factor-related protein-3 and ATP citrate lyase. Life sciences., 2022, 305120751

[63] Elseweidy MM, Elesawy AE, Sobh MS, et al. Ellagic acid ameliorates high fructose-induced hyperuricemia and non-alcoholic fatty liver in Wistar rats: Focusing on the role of C1q/tumor necrosis factor-related protein-3 and ATP citrate lyase. Life Sci. 2022:120751.

[64] Zhang J, Xu J, Lin X, et al.. CTRP3 ameliorates fructose-induced metabolic associated fatty liver disease via inhibition of xanthine oxidase-associated oxidative stress. Tissue Cell., 2021, 72101595

[65] Li JY, Wu GM, Hou Z, et al.. Expression of C1q/TNF-related protein-3 (CTRP3) in serum of patients with gestational diabetes mellitus and its relationship with insulin resistance. European review for medical and pharmacological sciences., 2017, 21(24): 5702-5710

[66] Maeda T. Alterations of hepatic gluconeogenesis and amino acid metabolism in CTRP3-deficient mice. Molecular biology reports., 2022, 49(2): 1617-1622

[67] Ono H, Shimano H, Katagiri H, et al.. Hepatic Akt activation induces marked hypoglycemia, hepatomegaly, and hypertriglyceridemia with sterol regulatory element binding protein involvement. Diabetes., 2003, 52(12): 2905-2913

[68] Miyake K, Ogawa W, Matsumoto M, et al.. Hyperinsulinemia, glucose intolerance, and dyslipidemia induced by acute inhibition of phosphoinositide 3-kinase signaling in the liver. J Clin Invest., 2002, 110(10): 1483-1491

[69] Asada S, Daitoku H, Matsuzaki H, et al.. Mitogen-activated protein kinases, Erk and p38, phosphorylate and regulate Foxo1. Cell Signal., 2007, 19(3): 519-527

[70] Shahiddoust F, Monazzami AA. Exercise-induced changes in insulin sensitivity, atherogenic index of plasma, and CTRP1/CTRP3 levels: the role of combined and high-intensity interval training in overweight and obese women. BMC Sports Science, Medicine and Rehabilitation., 2025, 17(1): 73

[71] Wang S, Ling Y, Liang W, et al.. Association of serum C1q/TNF-related protein-3 (CTRP-3) in patients with coronary artery disease. BMC cardiovascular disorders., 2017, 17(1210

[72] Yildirim A, Kucukosmanoglu M, Sumbul HE, et al.. Reduced CTRP3 levels in patients with stable coronary artery disease and related with the presence of paroxysmal atrial fibrillation. Arquivos brasileiros de cardiologia., 2022, 118(152-58

[73] Mourilhe-Rocha R, Bittencourt MI. CTRP-3 levels in patients with stable coronary artery disease and paroxysmal atrial fibrillation: a new potential biomarker in cardiovascular diseases. Arquivos brasileiros de cardiologia., 2022, 118(1): 59-60

[74] Liu D, Cui X, Lu R, et al.. CTRP3 is a coronary artery calcification biomarker and protects against vascular calcification by inhibiting β-catenin nuclear translocation to prevent vascular smooth muscle cell osteogenic differentiation. Journal of cardiology., 2022, 79(4): 551-558

[75] Yildirim A, Sumbul HE, Koca H, et al.. Complement C1q/tumor necrosis factor-related protein-3 (CTRP3) is significantly decreased in patients with heart failure and closely related with ventricular tachycardia. Acta Cardiol Sin., 2021, 37(3): 278-285

[76] Gao C, Zhao S, Lian K, et al.. C1q/TNF-related protein 3 (CTRP3) and 9 (CTRP9) concentrations are decreased in patients with heart failure and are associated with increased morbidity and mortality. BMC cardiovascular disorders., 2019, 19(1): 139

[77] Ma Z-G, Yuan Y-P, Zhang X, et al.. C1q-tumour necrosis factor-related protein-3 exacerbates cardiac hypertrophy in mice. Cardiovascular research., 2019, 115(61067-1077

[78] Liu Y, Li L-N, Guo S, et al.. Melatonin improves cardiac function in a mouse model of heart failure with preserved ejection fraction. Redox Biol., 2018, 18: 211-221

[79] Zhang Z, Zhu L, Feng P, et al.. C1q/tumor necrosis factor-related protein-3-engineered mesenchymal stromal cells attenuate cardiac impairment in mice with myocardial infarction. Cell death & disease., 2019, 10(7): 530

[80] Liu Y, Wu P, Xu X, et al.. C1q/TNF-related protein 3 alleviates heart failure via attenuation of oxidative stress in myocardial infarction rats. Peptides., 2023, 163170980

[81] Song Y, Zhang Y, Wan Z, et al.. CTRP3 alleviates myocardial ischemia/reperfusion injury in mice through activating LAMP1/JIP2/JNK pathway. Int Immunopharmacol., 2022, 107108681

[82] Choi KM, Hwang SY, Hong HC, et al.. Implications of C1q/TNF-related protein-3 (CTRP-3) and progranulin in patients with acute coronary syndrome and stable angina pectoris. Cardiovascular diabetology., 2014, 13: 14

[83] Liu Y, Wei C, Ding Z, et al.. Role of serum C1q/TNF-related protein family levels in patients with acute coronary syndrome. Frontiers In Cardiovascular Medicine., 2022, 9967918

[84] Demirtas D, Acıbucu F, Baylan FA, et al.. CTRP3 is significantly decreased in patients with primary hyperparathyroidism and closely related with osteoporosis. Exp Clin Endocrinol Diabetes., 2020, 128(3152-157

[85] Maghbooli Z, Hossein-Nezhad A, Khoshechin G, et al.. Possible association between circulating CTRP3 and knee osteoarthritis in postmenopausal women. Aging Clin Exp Res., 2019, 31(7927-934

[86] Murayama MA, Chi H-H, Matsuoka M, et al.. The CTRP3-AdipoR2 Axis regulates the development of experimental autoimmune encephalomyelitis by suppressing Th17 cell differentiation. Frontiers in immunology., 2021, 12607346

[87] Murayama MA, Kakuta S, Maruhashi T, et al.. CTRP3 plays an important role in the development of collagen-induced arthritis in mice. Biochemical and biophysical research communications., 2014, 443(1): 42-48

[88] Petersen PS, Wolf RM, Lei X, et al. Immunomodulatory roles of CTRP3 in endotoxemia and metabolic stress. Physiol Rep. 2016;4(5):e12735.

[89] Huang Y, Wan G, Tao J. C1q/TNF-related protein-3 exerts the chondroprotective effects in IL-1β-treated SW1353 cells by regulating the FGFR1 signaling. Biomed Pharmacother. 2017;85:41–46.

[90] Yokohama-Tamaki T, Maeda T, Tanaka TS, et al.. Functional analysis of CTRP3/cartducin in Meckel’s cartilage and developing condylar cartilage in the fetal mouse mandible. J Anat., 2011, 218(5): 517-533

[91] Cho Y, Kim H-S, Kang D, et al. CTRP3 exacerbates tendinopathy by dysregulating tendon stem cell differentiation and altering extracellular matrix composition. Sci Adv. 2021;7(47):eabg6069.

[92] Kim J-Y, Min J-Y, Baek JM, et al.. CTRP3 acts as a negative regulator of osteoclastogenesis through AMPK-c-Fos-NFATc1 signaling in vitro and RANKL-induced calvarial bone destruction in vivo. Bone., 2015, 79: 242-251

[93] Kim M-J, Park E-J, Lee W, et al.. Regulation of the transcriptional activation of CTRP3 in chondrocytes by c-Jun. Mol Cell Biochem., 2012, 368(1–2): 111-117

[94] Kong M, Gao Y, Guo X, et al.. Role of the CTRP family in tumor development and progression. Oncol Lett., 2021, 22(4): 723

[95] Akiyama H, Furukawa S, Wakisaka S, et al.. Elevated expression of CTRP3/cartducin contributes to promotion of osteosarcoma cell proliferation. Oncol Rep., 2009, 21(61477-1481

[96] Zhao G, Zhang L, Qian D, et al.. miR-495-3p inhibits the cell proliferation, invasion and migration of osteosarcoma by targeting C1q/TNF-related protein 3. Onco Targets Ther., 2019, 12: 6133-6143

[97] Zhang R, Guo C, Liu T, et al.. MicroRNA miR-495 regulates the development of Hepatocellular Carcinoma by targeting C1q/tumor necrosis factor-related protein-3 (CTRP3). Bioengineered., 2021, 12(1): 6902-6912

[98] Zhang H, Zhang-Sun Z-y, Xue C-x, et al. CTRP family in diseases associated with inflammation and metabolism: molecular mechanisms and clinical implication. Acta Pharmacol Sin. 2023;44(4):710–725.

Funding

National Natural Science Foundation of China(81873489)

RIGHTS & PERMISSIONS

The Author(s), under exclusive licence to the Huazhong University of Science and Technology