GDF11/TGFBR1 activation is essential for the antidepressant-like effect of H₂S: Role of suppressing the hippocampal cascade of necroptosis-neuroinflammation-Kynurenine pathway disorder

IF 2.7 3区医学 Q2 BEHAVIORAL SCIENCES

Physiology & Behavior Pub Date : 2026-03-15 Epub Date: 2026-01-10 DOI:10.1016/j.physbeh.2026.115227

Xiang Chen , Bo Wang , Yu-Hui Tang , Yi-Li Yi , Wei Zou , Xiao-Qing Tang , San-Qiao Yang

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Abstract

Background

Depression remains a major global health challenge, and current treatments are suboptimal. Hydrogen sulfide (H₂S), an endogenous gasotransmitter, has antidepressant potential; however, its mechanisms remain incompletely understood. Understanding the mechanisms underlying the antidepressant-like role of H₂S is essential for developing H₂S as a therapeutic candidate for treating depression.

Methods

Depressive-like behaviors were assessed via the open field test (OFT), novelty-suppressed feeding test (NSFT), sucrose preference test (SPT), tail suspension test (TST), and forced swim test (FST). Western blotting was used to analyze the protein expression levels. Cytokines (TNF-α, IL-1β, IL-4, IL-6, and IL-10) were quantified via ELISA. Kynurenine-pathway (KP) metabolites were assayed by selective reaction/multiple reaction monitoring technology.

Results

Chronic unpredictable mild stress (CUMS) reduced hippocampal growth differentiation factor 11 (GDF11) expression. H₂S significantly increased the expression of GDF11 and the ratio of p-Smad2/3/Smad2/3, a downstream effector of TGFBR1, indicating that H₂S enhances the activation of GDF11/TGFBR1 pathway in the hippocampus of CUMS-exposed rats. Furthermore, hippocampal GDF11 knockdown and pharmacological blockade of TGFBR1 with SB525334, which disrupts H₂S-induced activation of the GDF11/TGFBR1 pathway, reversed the molecular effects of H₂S in CUMS-exposed rats, including suppression of necroptosis, attenuation of neuroinflammation, and normalization of kynurenine-pathway enzymes and metabolites, as well as abolished the antidepressant-like effects of H₂S.

Conclusion

The hippocampal GDF11/TGFBR1 pathway mediates the antidepressant-like effects of H₂S by restraining the cascade of hippocampal necroptosis–neuroinflammation–KP disorder, suggesting that the GDF11/TGFBR1 pathway is a promising therapeutic target for depression.

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GDF11/TGFBR1激活是H₂S抗抑郁样作用的必要条件：抑制坏死性凋亡-神经炎症-犬尿氨酸通路障碍海马级联的作用

背景：抑郁症仍然是一个主要的全球健康挑战，目前的治疗是次优的。硫化氢（H₂S）是一种内源性气体递质，具有抗抑郁潜能；然而，其机制仍不完全清楚。了解H₂S抗抑郁作用的机制对于开发H₂S作为治疗抑郁症的候选药物至关重要。方法：采用开放性试验（OFT）、新奇性抑制进食试验（NSFT）、蔗糖偏好试验（SPT）、悬尾试验（TST）和强迫游泳试验（FST）评估抑郁样行为。Western blotting分析海马组织中RIPK3、p-RIPK3、p-RIPK1、p-MLKL蛋白表达水平及磷酸化-Smad2/3 （p-Smad2/3）与总Smad2/3的比值。ELISA法测定细胞因子（TNF-α、IL-1β、IL-4、IL-6、IL-10）含量。海马组织检测犬尿氨酸途径（KP）酶及其代谢物。结果：慢性不可预测轻度应激（CUMS）可降低海马生长分化因子11 （GDF11）的表达。H₂S显著提高TGFBR1的下游效应GDF11的表达和p-Smad2/3/Smad2/3比值，表明H₂S在cums暴露大鼠海马中激活了GDF11/TGFBR1通路。此外，用SB525334敲低海马GDF11和药物阻断TGFBR1，破坏h2s诱导的GDF11/TGFBR1通路的激活，逆转了cums暴露大鼠中h2s的分子效应，包括抑制坏死性坏死、神经炎症的衰减、犬尿氨酸通路酶和代谢物的正常化，并消除了h2s的抗抑郁样作用。结论：海马GDF11/TGFBR1通路通过抑制海马坏死坏死-神经炎症- kp紊乱级联介导H₂S的抗抑郁样作用，提示GDF11/TGFBR1通路是治疗抑郁症的一个有前景的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Physiology & Behavior 医学-行为科学

CiteScore

5.70

自引率

3.40%

发文量

274

审稿时长

47 days

期刊介绍： Physiology & Behavior is aimed at the causal physiological mechanisms of behavior and its modulation by environmental factors. The journal invites original reports in the broad area of behavioral and cognitive neuroscience, in which at least one variable is physiological and the primary emphasis and theoretical context are behavioral. The range of subjects includes behavioral neuroendocrinology, psychoneuroimmunology, learning and memory, ingestion, social behavior, and studies related to the mechanisms of psychopathology. Contemporary reviews and theoretical articles are welcomed and the Editors invite such proposals from interested authors.