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

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 HS 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.