HIPK2 protects neurons from oxidative stress and modulates central nervous system responses following traumatic brain injury

Articles in Press

Document Type : Original Article

Authors

1 Department of Neurosurgery, The Second Affiliated Hospital of Fujian Medical, Quanzhou, Fujian Province, China

2 Department of Neurosurgery, The Second Affiliated Hospital of Fujian Medical, Quanzhou , Fujian Province, China

3 Department of Intensive Care Unit, The Second Affiliated Hospital of Fujian Medical, Quanzhou, Fujian Province, China

10.22038/ijbms.2026.90522.19511

Abstract

Objective(s): Traumatic brain injury (TBI) induces oxidative stress, contributing to secondary neuronal damage. This study aimed to elucidate the role of the stress-responsive kinase HIPK2 in regulating endogenous antioxidant defenses in neural tissue following TBI.
Materials and Methods: We employed complementary in vitro and in vivo models: an H₂O₂-induced oxidative stress model in PC12 cells (with HIPK2 inhibited by tBID) and a controlled cortical impact mouse model of TBI (with HIPK2 overexpressed via intracerebroventricular Ad-HIPK2 injection). Analyses included assessments of cell viability, mRNA expression, and protein levels of key antioxidant factors (HO-1, UGT1A1, NQO1).
Results: In vitro, HIPK2 inhibition markedly increased oxidative stress-induced cell death and significantly down-regulated UGT1A1 expression. In vivo, endogenous HIPK2 expression was significantly suppressed post-TBI. Conversely, HIPK2 overexpression effectively rescued the expression of antioxidant proteins UGT1A1 and NQO1. 
Conclusion: These results demonstrate that HIPK2 is a critical modulator of the antioxidant response after TBI, capable of orchestrating key defense genes and conferring neuroprotection. Our findings identify HIPK2 as a promising molecular target for therapeutic intervention against TBI-related oxidative damage.

Keywords

Main Subjects

References

1. Kabadi S, Faden A. Neuroprotective strategies for traumatic brain injury: improving clinical translation. Int J Mol Sci 2014;15:1216-1236. 
2. Rosenfeld JV, Maas AI, Bragge P, Morganti-Kossmann MC, Manley GT, Gruen RL. Early management of severe traumatic brain injury. Lancet 2012;380:1088-1098. 
3. Hazeldine J, Lord JM, Belli A. Traumatic brain injury and peripheral immune suppression: Primer and prospectus. Front Neurol 2015;6:235. 
4. Maas AIR, Menon DK, Adelson PD, Andelic N, Bell MJ, Belli A, et al. Traumatic brain injury: Integrated approaches to improve prevention, clinical care, and research. Lancet Neurol 2017;16:987-1048. 
5. Chiang S, Chen S, Chang L. The role of ho-1 and its crosstalk with oxidative stress in cancer cell survival. Cells 2021;10:2401. 
6. Zhang R, Xu M, Wang Y, Xie F, Zhang G, Qin X. Nrf2—a promising therapeutic target for defensing against oxidative stress in stroke. Mol Neurobiol 2017;54:6006-6017. 
7. Radermacher KA, Wingler K, Langhauser F, Altenhofer S, Kleikers P, Hermans JJ, et al. Neuroprotection after stroke by targeting nox4 as a source of oxidative stress. Antioxid Redox Signal 2013;18:1418-1427. 
8. Chen X, Wang H, Zhou M, Li X, Fang Z, Gao H, et al. Valproic acid attenuates traumatic brain injury-induced inflammation in vivo: involvement of autophagy and the nrf2/are signaling pathway. Front Mol Neurosci 2018;11:117. 
9. Buckley DB, Klaassen CD. Induction of mouse udp-glucuronosyltransferase mrna expression in liver and intestine by activators of aryl-hydrocarbon receptor, constitutive androstane receptor, pregnane x receptor, peroxisome proliferator-activated receptor α, and nuclear factor erythroid 2-related factor 2. Drug Metab Dispos 2009;37:847-856. 
10.    Wang Y, Sun W, Du B, Miao X, Bai Y, Xin Y, et al. Therapeutic effect of mg-132 on diabetic cardiomyopathy is associated with its suppression of proteasomal activities: roles of nrf2 and nf-κb. Am J Physiol-Heart C 2013;304:H567-H578. 
11.    Roth TL, Nayak D, Atanasijevic T, Koretsky AP, Latour LL, McGavern DB. Transcranial amelioration of inflammation and cell death after brain injury. Nature 2014;505:223-228. 
12.    Tavazzi B, Signoretti S, Lazzarino G, Amorini AM, Delfini R, Cimatti M, et al. Cerebral oxidative stress and depression of energy metabolism correlate with  severity of diffuse brain injury in rats. Neurosurgery 2005;56:582-589 
13.    Wefers H, Komai T, Talalay P, Sies H. Protection against reactive oxygen species by nad(p)h: quinone reductase induced  by the dietary antioxidant butylated hydroxyanisole (bha). Decreased hepatic  low-level chemiluminescence during quinone redox cycling. Febs Lett 1984;169:63-66. 
14.    Yachie A. Heme oxygenase-1 deficiency and oxidative stress: A review of 9 independent human cases and animal models. Int J Mol Sci 2021;22:1514. 
15.    Wook CD, Yong CC. Hipk2 modification code for cell death and survival. Mol Cell Oncol 2014;1:e955999. 
16.    de la Vega L, Grishina I, Moreno R, Kruger M, Braun T, Schmitz ML. A redox-regulated sumo/acetylation switch of hipk2 controls the survival threshold to oxidative stress. Mol Cell 2012;46:472-483. 
17.    Hofmann TG, Jaffray E, Stollberg N, Hay RT, Will H. Regulation of homeodomain-interacting protein kinase 2 (hipk2) effector function  through dynamic small ubiquitin-related modifier-1 (sumo-1) modification. J Biol Chem 2005;280:29224-29232. 
18.    Saul VV, de la Vega L, Milanovic M, Krüger M, Braun T, Fritz-Wolf K, et al. Hipk2 kinase activity depends on cis-autophosphorylation of its activation loop. J Mol Cell Biol 2013;5:27-38. 
19.    Saul VV, Schmitz ML. Posttranslational modifications regulate hipk2, a driver of proliferative diseases. J Mol Med (Berl). 2013;91:1051-1058. 
20.    de la Vega L, Grishina I, Moreno R, Krüger M, Braun T, Schmitz ML. A redox-regulated sumo/acetylation switch of hipk2 controls the survival threshold to oxidative stress. Mol Cell 2012;46:472-483. 
21.    Li R, Shang J, Zhou W, Jiang L, Xie D, Tu G. Overexpression of hipk2 attenuates spinal cord injury in rats by modulating apoptosis, oxidative stress, and inflammation. Biomed Pharmacother 2018;103:127-134. 
22.    Wiatrak B, Kubis-Kubiak A, Piwowar A, Barg E. Pc12 cell line: cell types, coating of culture vessels, differentiation and other culture conditions. Cells-Basel 2020;9:958. 
23.    Taylor S, Wakem M, Dijkman G, Alsarraj M, Nguyen M. A practical approach to rt-qpcr-publishing data that conform to the miqe  guidelines. Methods 2010;50:S1-S5. 
24.    Osier N, Dixon CE. The controlled cortical impact model of experimental brain trauma: Overview, research applications, and protocol. Methods Mol Biol  2016;1462:177-192. 
25.    Loane DJ, Byrnes KR. Role of microglia in neurotrauma. Neurotherapeutics 2010;7:366-377. 
26.    Hopp S, Nolte MW, Stetter C, Kleinschnitz C, Sirén A, Albert-Weissenberger C. Alleviation of secondary brain injury, posttraumatic inflammation, and brain edema formation by inhibition of factor xiia. J Neuroinflamm 2017;14:39. 
27.    Verweij BH, Muizelaar JP, Vinas FC, Peterson PL, Xiong Y, Lee CP. Impaired cerebral mitochondrial function after traumatic brain injury in humans. J Neurosurg 2000;93:815-820. 
28.    Roth TL, Nayak D, Atanasijevic T, Koretsky AP, Latour LL, McGavern DB. Transcranial amelioration of inflammation and cell death after brain injury. Nature 2014;505:223-228. 
29.    Kahles T, Brandes RP. Nadph oxidases as therapeutic targets in ischemic stroke. Cell Mol Life Sci 2012;69:2345-2363. 
30.    Ouyang YB, Stary CM, White RE, Giffard RG. The use of micrornas to modulate redox and immune response to stroke. Antioxid Redox Signal 2015;22:187-202. 
31.    Dinkova-Kostova AT, Talalay P. Nad(p)h:Quinone acceptor oxidoreductase 1 (nqo1), a multifunctional antioxidant  enzyme and exceptionally versatile cytoprotector. Arch Biochem Biophys 2010;501:116-123. 
32.    Prochaska HJ, Talalay P, Sies H. Direct protective effect of nad(p)h:Quinone reductase against menadione-induced  chemiluminescence of postmitochondrial fractions of mouse liver. J Biol Chem 1987;262:1931-1934. 
33.    Ross D, Siegel D. The diverse functionality of nqo1 and its roles in redox control. Redox Biol 2021;41:101950. 
34.    Siegel D, Gustafson DL, Dehn DL, Han JY, Boonchoong P, Berliner LJ, et al. Nad(p)h:quinone oxidoreductase 1: role as a superoxide scavenger. Mol Pharmacol 2004;65:1238-1247. 
35.    Raina AK, Templeton DJ, Deak JC, Perry G, Smith MA. Quinone reductase (nqo1), a sensitive redox indicator, is increased in alzheimer’s disease. Redox Rep 1999;4:23-27. 
36.    Loboda A, Damulewicz M, Pyza E, Jozkowicz A, Dulak J. Role of nrf2/ho-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci 2016;73:3221-3247. 
37.    Ryter SW. Heme oxgenase-1, a cardinal modulator of regulated cell death and inflammation. Cells-Basel 2021;10:515.
38.    Sardina F, Conte A, Paladino S, Pierantoni GM, Rinaldo C. Hipk2 in the physiology of nervous system and its implications in neurological disorders. Biochim Biophys Acta Mol Cell Res  2023;1870:119465. 
39.    Sung KS, Lee Y, Kim ET, Lee S, Ahn J, Choi CY. Role of the sumo-interacting motif in hipk2 targeting to the pml nuclear bodies and regulation of p53. Exp Cell Res 2011;317:1060-1070. 
40.    Zou F, Xu J, Fu H, Cao J, Mao H, Gong M, et al. Different functions of hipk2 and ctbp2 in traumatic brain injury. J Mol Neurosci 2013;49:395-408. 
41.    Moehlenbrink J, Bitomsky N, Hofmann TG. Hypoxia suppresses chemotherapeutic drug-induced p53 serine 46 phosphorylation by triggering hipk2 degradation. Cancer Lett 2010;292:119-124. 
Iranian Journal of Basic Medical Sciences

Articles in Press, Accepted Manuscript
Available Online from 20 April 2026

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