Evidence map›Paper›PMID 41332349›Full record

ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2026

Discovery of a Novel and Potent Kir4.1 Inhibitor as a Safe and Rapid-Onset Antidepressant Agent in Mice.

Sisi Wang, Xiaoyu Zhou, Mengdan Li, Chao Zhang, Haiyan Xu, Jingyi He, Li Zhan, Yueling Gu, Hao Gu, Tianyu Tu and 6 more

Erratum issuedAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Article
  2. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

16 authors.

Sisi WangState Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
Xiaoyu ZhouState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Mengdan LiState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Chao ZhangState Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
Haiyan XuState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Jingyi HeState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Li ZhanState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Yueling GuState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Hao GuState Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
Tianyu TuState Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
Hanfang LiuState Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
Taotao LuState Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
Yueming ZhengState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Jian LiState Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.ORCID https://orcid.org/0000-0002-7521-8798
Zhaobing GaoState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Yixiang XuState Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.

Funding

Chinese Special Fund for State Key Laboratory of Bioreactor Engineering 2060204Innovative Research Team of High-level Local University in Shanghai SHSMU-ZDCX20212702National key R&D Program of China 2021YFA0804904National Postdoctoral Program for Innovative Talents BX20240397National Science Fund for Distinguished Young Scholars 82404594Postdoctoral Research Foundation of China 2024M753376Shanghai Frontier Science Center of Optogenetic Techniques for Cell Metabolism 2021 SciShanghai Frontier Science Center of Optogenetic Techniques for Cell Metabolism Tech 03-28Strategic Priority Research Program of the Chinese Academy of Sciences XDB0830403
6 · The paper itself

Abstract

Major depressive disorder is a serious psychiatric disorder for which novel and fast-acting antidepressants are required. Targeted inhibition of the astrocytic inwardly rectifying potassium channel 4.1 (Kir4.1) in the lateral habenula could rapidly alleviate depression-like behaviors. A previous study identified Kir4.1 as a promising target for achieving rapid-onset antidepressant effects. The aim of this study is to identify novel Kir4.1 inhibitors with good druggability through structural modification of the lead compound EHop-016, resulting in fifty derivatives. Among these, JX3212 exhibits the most potent in vitro inhibitory activity against Kir4.1, with acceptable selectivity and excellent brain exposure. Notably, a single administration of JX3212 results in rapid-onset antidepressant effects within 1 h in multiple rodent models of depression, with comparable efficacy to (S)-ketamine; this inhibitor-like effect is abolished in mice with tamoxifen-induced conditional Kir4.1 knockout in astrocytes. Additionally, JX3212 demonstrates superior safety margins compared to both (S)-ketamine and the conventional antidepressant imipramine in murine behavioral assays. In summary, JX3212 functions as a selective Kir4.1 inhibitor with favorable druggability and stable antidepressant efficacy in preclinical models. This pharmacological profile supports the further development of JX3212 as a promising therapeutic candidate for major depressive disorder.

Indexed as

Antidepressive AgentsDepressionMajor Depressive DisorderPotassium Channels, Inwardly RectifyingAnimalsAstrocytesDisease Models, AnimalHumansKcnj10 ChannelMaleMiceMice, Inbred C57BLMice, KnockoutAntidepressive AgentsKcnj10 ChannelPotassium Channels, Inwardly RectifyingdepressionKir4.1 inhibitorsrapid‐onset(S)‐ketaminestructural repurposing

Identifiers

PMID41332349
PMCPMC12903969

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.