Hydrogen Sulfide (H<sub>2</sub>S) Mitigates Sepsis-Induced Adrenal Dysfunction via Inhibition of TNFα-Mediated Necroptosis
Background: Sepsis is a life-threatening condition that is characterized by systemic inflammation and organ dysfunction, with adrenal dysfunction being a significant complication. This study aimed to investigate the role of necroptosis and hydrogen sulfide (H<sub>2</sub>S) in sepsis-indu...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-04-01
|
| Series: | Pathogens |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-0817/14/5/439 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850126186563239936 |
|---|---|
| author | Kai Ma Jingwen Huang Jin Zhang Yuan Tian Jing Hu Linhao Ma Changnan Wang |
| author_facet | Kai Ma Jingwen Huang Jin Zhang Yuan Tian Jing Hu Linhao Ma Changnan Wang |
| author_sort | Kai Ma |
| collection | DOAJ |
| description | Background: Sepsis is a life-threatening condition that is characterized by systemic inflammation and organ dysfunction, with adrenal dysfunction being a significant complication. This study aimed to investigate the role of necroptosis and hydrogen sulfide (H<sub>2</sub>S) in sepsis-induced adrenal dysfunction. Methods: A cecal ligation and puncture (CLP)-induced sepsis mouse model was employed. Adrenocortical-specific mixed lineage kinase domain-like pseudokinase (MLKL) knockout (MLKL-KO) and cystathioneine β-synthase (CBS) knockout (CBS-KO) mice were generated using Cre-loxP technology and adrenocortical-specific Cre tool mice. In vitro experiments utilized TNFα-stimulated Y1 adrenocortical cells. The treatments included the H<sub>2</sub>S donor NaHS, TNFα inhibitor R-7050, necroptosis inhibitor NSA and CBS inhibitor AOAA. Pathological assessment involved hematoxylin–eosin (H&E) staining and a Western blot analysis of necroptosis markers (the phosphorylation of MLKL (p-MLKL) and phosphorylation of receptor-interacting protein kinases 1 (p-RIPK1)). Results: Sepsis induced adrenal congestion, elevated TNFα levels, and activated necroptosis (increased p-MLKL/p-RIPK1) in wild-type mice. H<sub>2</sub>S treatment attenuated adrenal damage, reduced TNFα, and suppressed necroptosis. MLKL knockout reduced septic adrenal dysfunction, whereas CBS knockout exacerbated septic adrenal dysfunction. In vitro, TNFα induced Y1 cell necroptosis, which was reversed by H<sub>2</sub>S or NSA. AOAA exacerbated TNFα-induced necroptosis in Y1 cells. Conclusions: H<sub>2</sub>S inhibits TNFα-mediated necroptosis, thereby preserving adrenal integrity in sepsis. Targeting the TNFα–necroptosis axis and enhancing endogenous H<sub>2</sub>S production may represent novel therapeutic strategies for sepsis-associated adrenal dysfunction. |
| format | Article |
| id | doaj-art-e6df1ecbf45b4f1ea0c6fd0bc06caacc |
| institution | OA Journals |
| issn | 2076-0817 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pathogens |
| spelling | doaj-art-e6df1ecbf45b4f1ea0c6fd0bc06caacc2025-08-20T02:33:58ZengMDPI AGPathogens2076-08172025-04-0114543910.3390/pathogens14050439Hydrogen Sulfide (H<sub>2</sub>S) Mitigates Sepsis-Induced Adrenal Dysfunction via Inhibition of TNFα-Mediated NecroptosisKai Ma0Jingwen Huang1Jin Zhang2Yuan Tian3Jing Hu4Linhao Ma5Changnan Wang6Lab of Stress Injury, School of Life Sciences, Shanghai University, Shanghai 200444, ChinaLab of Stress Injury, School of Life Sciences, Shanghai University, Shanghai 200444, ChinaGeneral Practice Department, Shanghai Pudong New District Kangqiao Community Health Service Center, Shanghai 201315, ChinaLab of Stress Injury, School of Life Sciences, Shanghai University, Shanghai 200444, ChinaLab of Stress Injury, School of Life Sciences, Shanghai University, Shanghai 200444, ChinaDepartment of Emergency Medicine, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai 200081, ChinaLab of Stress Injury, School of Life Sciences, Shanghai University, Shanghai 200444, ChinaBackground: Sepsis is a life-threatening condition that is characterized by systemic inflammation and organ dysfunction, with adrenal dysfunction being a significant complication. This study aimed to investigate the role of necroptosis and hydrogen sulfide (H<sub>2</sub>S) in sepsis-induced adrenal dysfunction. Methods: A cecal ligation and puncture (CLP)-induced sepsis mouse model was employed. Adrenocortical-specific mixed lineage kinase domain-like pseudokinase (MLKL) knockout (MLKL-KO) and cystathioneine β-synthase (CBS) knockout (CBS-KO) mice were generated using Cre-loxP technology and adrenocortical-specific Cre tool mice. In vitro experiments utilized TNFα-stimulated Y1 adrenocortical cells. The treatments included the H<sub>2</sub>S donor NaHS, TNFα inhibitor R-7050, necroptosis inhibitor NSA and CBS inhibitor AOAA. Pathological assessment involved hematoxylin–eosin (H&E) staining and a Western blot analysis of necroptosis markers (the phosphorylation of MLKL (p-MLKL) and phosphorylation of receptor-interacting protein kinases 1 (p-RIPK1)). Results: Sepsis induced adrenal congestion, elevated TNFα levels, and activated necroptosis (increased p-MLKL/p-RIPK1) in wild-type mice. H<sub>2</sub>S treatment attenuated adrenal damage, reduced TNFα, and suppressed necroptosis. MLKL knockout reduced septic adrenal dysfunction, whereas CBS knockout exacerbated septic adrenal dysfunction. In vitro, TNFα induced Y1 cell necroptosis, which was reversed by H<sub>2</sub>S or NSA. AOAA exacerbated TNFα-induced necroptosis in Y1 cells. Conclusions: H<sub>2</sub>S inhibits TNFα-mediated necroptosis, thereby preserving adrenal integrity in sepsis. Targeting the TNFα–necroptosis axis and enhancing endogenous H<sub>2</sub>S production may represent novel therapeutic strategies for sepsis-associated adrenal dysfunction.https://www.mdpi.com/2076-0817/14/5/439sepsisadrenal dysfunctionnecroptosisgene knockout micehydrogen sulfideTNFα |
| spellingShingle | Kai Ma Jingwen Huang Jin Zhang Yuan Tian Jing Hu Linhao Ma Changnan Wang Hydrogen Sulfide (H<sub>2</sub>S) Mitigates Sepsis-Induced Adrenal Dysfunction via Inhibition of TNFα-Mediated Necroptosis Pathogens sepsis adrenal dysfunction necroptosis gene knockout mice hydrogen sulfide TNFα |
| title | Hydrogen Sulfide (H<sub>2</sub>S) Mitigates Sepsis-Induced Adrenal Dysfunction via Inhibition of TNFα-Mediated Necroptosis |
| title_full | Hydrogen Sulfide (H<sub>2</sub>S) Mitigates Sepsis-Induced Adrenal Dysfunction via Inhibition of TNFα-Mediated Necroptosis |
| title_fullStr | Hydrogen Sulfide (H<sub>2</sub>S) Mitigates Sepsis-Induced Adrenal Dysfunction via Inhibition of TNFα-Mediated Necroptosis |
| title_full_unstemmed | Hydrogen Sulfide (H<sub>2</sub>S) Mitigates Sepsis-Induced Adrenal Dysfunction via Inhibition of TNFα-Mediated Necroptosis |
| title_short | Hydrogen Sulfide (H<sub>2</sub>S) Mitigates Sepsis-Induced Adrenal Dysfunction via Inhibition of TNFα-Mediated Necroptosis |
| title_sort | hydrogen sulfide h sub 2 sub s mitigates sepsis induced adrenal dysfunction via inhibition of tnfα mediated necroptosis |
| topic | sepsis adrenal dysfunction necroptosis gene knockout mice hydrogen sulfide TNFα |
| url | https://www.mdpi.com/2076-0817/14/5/439 |
| work_keys_str_mv | AT kaima hydrogensulfidehsub2subsmitigatessepsisinducedadrenaldysfunctionviainhibitionoftnfamediatednecroptosis AT jingwenhuang hydrogensulfidehsub2subsmitigatessepsisinducedadrenaldysfunctionviainhibitionoftnfamediatednecroptosis AT jinzhang hydrogensulfidehsub2subsmitigatessepsisinducedadrenaldysfunctionviainhibitionoftnfamediatednecroptosis AT yuantian hydrogensulfidehsub2subsmitigatessepsisinducedadrenaldysfunctionviainhibitionoftnfamediatednecroptosis AT jinghu hydrogensulfidehsub2subsmitigatessepsisinducedadrenaldysfunctionviainhibitionoftnfamediatednecroptosis AT linhaoma hydrogensulfidehsub2subsmitigatessepsisinducedadrenaldysfunctionviainhibitionoftnfamediatednecroptosis AT changnanwang hydrogensulfidehsub2subsmitigatessepsisinducedadrenaldysfunctionviainhibitionoftnfamediatednecroptosis |