Discovery of a novel Nrf2 activator that modulates mitochondrial function in neurons by regulating DHRS3-Nrf2 interaction after ischemic stroke.
Overview
- School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China
- State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong, 264003, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
Abstract
Rationale: Given the crucial role of the Nrf2 pathway in cellular adaptability to stress, targeting small-molecule activation of Nrf2 represents a promising therapeutic strategy for acute ischemic stroke (AIS). However, the clinical translation of existing Nrf2 activators is hindered by adverse effects, such as liver damage, and none are currently approved for AIS. Therefore, we aimed to develop a novel Nrf2 activator that specifically activates neuronal Nrf2 while mitigating adverse effects, with the goal of providing a lead compound for AIS.
Methods: We validated the anti-AIS effects and mitochondrial protective functions of the novel Nrf2 activator Cpd.51 through multiple in vivo and in vitro experiments. Mechanistic studies involving surface plasmon resonance, cellular thermal shift assay, co-immunoprecipitation, chromatin immunoprecipitation, GST pull-down, and RNA sequencing were used to determine how Cpd.51 activates Nrf2. A comparative toxicological evaluation was conducted to demonstrate its superior safety profile over parent compound (Omaveloxolone).
Results: Cpd.51 exhibited favorable blood-brain barrier permeability, improved safety profile, enhanced mitochondrial function protection and significant neuroprotective effect through the specific activation of neuronal Nrf2. Mechanistically, Cpd.51 interacted with Cys151 and Gly148 in the BTB domain of Keap1, inhibiting Nrf2 degradation, consequently suppressing the transcription of its downstream target DHRS3, a member of the short-chain dehydrogenase/
Conclusions: Our work identified Cpd.51 as a novel and safe Nrf2 activator and unveils a unique feedback mechanism involving Nrf2-DHRS3 interaction, providing a new therapeutic avenue for AIS.
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.
The paper's code and data availability statement is in the Data section.
Tracing map
A tracing map links a paper to the code its authors published: this paper has none (its code is available on request), so it has no map.
Data
No dataset and no data link were found in the paper.
Data and code availability
All data reported in this paper will be shared by the lead contact upon request. This paper does not report original code.
Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 1, 30 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 15 authors, 6 keywords, 12 MeSH terms, 2 funders, 84 references, 4 RRIDs.
Cite
This paper
Sun, X., Liu, Z., An, H., Xu, H., Zou, F., Lu, J., Zhang, X., Han, X., Song, Z., Sun, Y., Wang, W., Wang, H., Zhang, J., Wang, Y., & Tian, J. (2026). Discovery of a novel Nrf2 activator that modulates mitochondrial function in neurons by regulating DHRS3-Nrf2 interaction after ischemic stroke. Theranostics, 16(10), 5713-5740. https://
BibTeX
@article{sun2026discover
author = {Sun, Xiaohui and Liu, Zhaofeng and An, Huanhuan and Xu, Hengwei and Zou, Fangxia and Lu, Jing and Zhang, Xiaofan and Han, Xinyu and Song, Ziwei and Sun, Yanli and Wang, Wenyan and Wang, Hongbo and Zhang, Jianzhao and Wang, Yunjie and Tian, Jingwei},
title = {{Discovery of a novel Nrf2 activator that modulates mitochondrial function in neurons by regulating DHRS3-Nrf2 interaction after ischemic stroke}},
journal = {Theranostics},
year = {2026},
month = mar,
volume = {16},
number = {10},
pages = {5713--5740},
publisher = {Ivyspring International Publisher},
issn = {1838-7640},
doi = {10.7150/
url = {https://
pmid = {41993611},
pmcid = {PMC13081163}
}
RIS
TY - JOUR
AU - Sun, Xiaohui
AU - Liu, Zhaofeng
AU - An, Huanhuan
AU - Xu, Hengwei
AU - Zou, Fangxia
AU - Lu, Jing
AU - Zhang, Xiaofan
AU - Han, Xinyu
AU - Song, Ziwei
AU - Sun, Yanli
AU - Wang, Wenyan
AU - Wang, Hongbo
AU - Zhang, Jianzhao
AU - Wang, Yunjie
AU - Tian, Jingwei
TI - Discovery of a novel Nrf2 activator that modulates mitochondrial function in neurons by regulating DHRS3-Nrf2 interaction after ischemic stroke
T2 - Theranostics
J2 - Theranostics
PY - 2026
DA - 2026/
VL - 16
IS - 10
SP - 5713
EP - 5740
SN - 1838-7640
PB - Ivyspring International Publisher
DO - 10.7150/
UR - https://
LA - en
ER -
CSL-JSON
{
"id": "10.7150/
"type": "article-journal",
"title": "Discovery of a novel Nrf2 activator that modulates mitochondrial function in neurons by regulating DHRS3-Nrf2 interaction after ischemic stroke",
"container-title": "Theranostics",
"author": [
{
"family": "Sun",
"given": "Xiaohui"
},
{
"family": "Liu",
"given": "Zhaofeng"
},
{
"family": "An",
"given": "Huanhuan"
},
{
"family": "Xu",
"given": "Hengwei"
},
{
"family": "Zou",
"given": "Fangxia"
},
{
"family": "Lu",
"given": "Jing"
},
{
"family": "Zhang",
"given": "Xiaofan"
},
{
"family": "Han",
"given": "Xinyu"
},
{
"family": "Song",
"given": "Ziwei"
},
{
"family": "Sun",
"given": "Yanli"
},
{
"family": "Wang",
"given": "Wenyan"
},
{
"family": "Wang",
"given": "Hongbo"
},
{
"family": "Zhang",
"given": "Jianzhao"
},
{
"family": "Wang",
"given": "Yunjie"
},
{
"family": "Tian",
"given": "Jingwei"
}
],
"container-title-short":
"volume": "16",
"issue": "10",
"page": "5713-5740",
"DOI": "10.7150/
"PMID": "41993611",
"PMCID": "PMC13081163",
"ISSN": "1838-7640",
"publisher": "Ivyspring International Publisher",
"URL": "https://
"language": "en",
"issued": {
"date-parts": [
[
2026,
3,
30
]
]
}
}
Similar papers
The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.
- [1] doi:10.1186/s10020-024-00995-5
- Triolein alleviates ischemic stroke brain injury by regulating autophagy and inflammation through the AKT/
mTOR signaling pathway. Journal: Molecular medicine (Cambridge, Mass.)In common: stroke, mouse, cellular / molecular, 3 references - [2] doi:10.1016/j.isci.2026.115779
- Propranolol alleviates cerebral infarction through the β2-AR-mediated ERK/
NLRP3 pathway. Journal: iScienceIn common: stroke, mouse, cellular / molecular, 3 references - [3] doi:10.1007/s00018-025-05804-8
- Piezo1 disrupts blood-brain barrier via CaMKII/
Nrf2 in ischemic stroke. Journal: Cellular and molecular life sciences : CMLSIn common: stroke, mouse, cellular / molecular, 3 references - [4] doi:10.3390/biomedicines14020375
- Comprehensive Analysis of Immune-Related Mitochondrial Genes in Ischemic Stroke Through Integrated Bioinformatics and Validation.Journal: BiomedicinesIn common: stroke, cellular / molecular, 3 references
- [5] doi:10.1186/s12974-024-03302-5
- Synergistic effects of repeated transcranial magnetic stimulation and mesenchymal stem cells transplantation on alleviating neuroinflammation and PANoptosis in cerebral ischemia.Journal: Journal of neuroinflammationIn common: stroke, cellular / molecular, 3 references
- [6] doi:10.1002/advs.202524087
- Gm26550 Modulates Learning and Memory by Increasing IGF1 mRNA Expression and Stability in Nrf2<sup>-/
-</ sup> Mice. Journal: Advanced science (Weinheim, Baden-Wurttemberg, Germany)In common: mouse, 3 references - [7] doi:10.1007/s10565-026-10177-0
- Multi-omics analysis and experimental validation reveal the IRF7-CXCL10 axis as a master regulator of microglial PCD in ischemic stroke.Journal: Cell biology and toxicologyIn common: stroke, mouse, cellular / molecular, 3 references
- [8] doi:10.1097/md.0000000000041396
- The roles of STAT1, CASP8, and MYD88 in the care of ischemic stroke.Journal: MedicineIn common: stroke, cellular / molecular, 2 references
- [9] doi:10.1002/jnr.70130
- Pantothenic Acid Protects Neurons After Ischemic Stroke by Targeting ID3 to Restore Action Potential Amplitude.Journal: Journal of neuroscience researchIn common: stroke, mouse, cellular / molecular, 2 references
- [10] doi:10.3389/fneur.2026.1733679 [code]
- M2 macrophage-derived exosomes mitigate acute inflammation following ischemic stroke.Journal: Frontiers in neurologyIn common: stroke, mouse, cellular / molecular, 2 references
Contribute
The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.
Sign in with ORCID to claim this paper as one of its authors, correct its record or validate its tracing map: when the paper's metadata lists your ORCID iD, you are recognized at once. Maintainers of its code: sign in with GitHub, then claim the repository on your account page.
Claim this paper
Correct its record
Say what each link of this record is, remove the ones that are not the paper's, add the ones that are missing. The correction becomes a new version of the record, in its Versions section.
Request its removal
To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).
Discussion, reproductions, activity
Discussion: code errors and mismatches between the code and the paper about this paper and its code, from readers and its authors, beside the paper and its tracing map.
Reproductions: reports from readers who ran the authors' code and did not get the paper's result, what they ran, with which environment, commit and data.
Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.