1-Methylhistidine attenuates early myocardial inflammation in type 3 cardiorenal syndrome through modulation of the p105/p50 NF-κB axis
- 1Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin Medical University
- 2Department of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin Medical University
Abstract
Type 3 cardiorenal syndrome (CRS3) is characterized by cardiac injury or dysfunction secondary to acute kidney injury (AKI), yet the contribution of AKI-associated metabolic remodeling to early myocardial inflammation remains poorly understood. Here, paired serum and myocardial untargeted metabolomics identified 1-methylhistidine (1-MH) as a metabolite elevated in both compartments, with the highest variable importance in projection score in serum. Exogenous 1-MH improved the E/A ratio and attenuated myocardial inflammation and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) positivity in rats with CRS3. Similar protective effects were observed in a separate post-ischemic cohort in which 1-MH was administered immediately after renal reperfusion. In CRS serum-exposed H9c2 cells, 1-MH reduced reactive oxygen species-associated fluorescence, malondialdehyde content, and intracellular Fe ²⁺ levels. Transcriptomic profiling showed that 1-MH suppressed inflammatory signaling, accompanied by changes in oxidative metabolism. Integration of these transcriptomic signatures with target prediction prioritized NFKB1/p105, while ensemble docking identified recurrent candidate interaction regions within p105. Cellular thermal shift assays showed a concentration-related increase in p105 thermal stability following 1-MH treatment. 1-MH increased p105 abundance while reducing total p50 abundance and nuclear p50 accumulation. p105 overexpression increased p50 abundance and the expression of inflammatory transcripts and proteins suppressed by 1-MH. These findings demonstrate that 1-MH attenuates early myocardial inflammation in CRS3 and reduces oxidative stress-related changes in CRS serum-exposed H9c2 cells. These functional results support modulation of the p105/p50 NF-κB axis and identify p105 as a molecular link between AKI-associated metabolic remodeling and myocardial inflammatory signaling.
Related
- Previous malaria exposure attenuates monocyte-driven inflammation and correlates with modulation of the B cell response
- “Radiation-Synthesized Gallotannin Hydrogel Attenuates Trisenox-Induced Nephrotoxicity in Rats: miR-223/TXNIP Axis Modulation of Oxidative Stress and Inflammation”
- Tragopogon coelesyriacus Boiss. attenuates ethanol-induced gastric ulcer in vivo: modulation of oxidative stress, inflammation, and apoptosis
- Dapagliflozin Attenuates Post-Infarction Myocardial Fibrosis Associated With the Inhibition of NLRP3-Dependent Inflammation
- Pterostilbene attenuates VCD-induced ovarian damage through modulation of oxidative stress, inflammation, apoptosis, and SIRT1/FOXO3a gene expression
BibTeX
@article{zhang20261methylhistidine,
title = {{1-Methylhistidine attenuates early myocardial inflammation in type 3 cardiorenal syndrome through modulation of the p105/p50 NF-κB axis}},
author = {Jiakun Zhang and Qian Wang and Xingyi Tu and Han Zhou and Shihui Wang and Jingjie Li},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1974807},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1974807/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - 1-Methylhistidine attenuates early myocardial inflammation in type 3 cardiorenal syndrome through modulation of the p105/p50 NF-κB axis
AU - Jiakun Zhang
AU - Qian Wang
AU - Xingyi Tu
AU - Han Zhou
AU - Shihui Wang
AU - Jingjie Li
PY - 2026
DA - 2026/10/14
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1974807
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1974807/full
AB - Type 3 cardiorenal syndrome (CRS3) is characterized by cardiac injury or dysfunction secondary to acute kidney injury (AKI), yet the contribution of AKI-associated metabolic remodeling to early myocardial inflammation remains poorly understood. Here, paired serum and myocardial untargeted metabolomics identified 1-methylhistidine (1-MH) as a metabolite elevated in both compartments, with the highest variable importance in projection score in serum. Exogenous 1-MH improved the E/A ratio and attenuated myocardial inflammation and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) positivity in rats with CRS3. Similar protective effects were observed in a separate post-ischemic cohort in which 1-MH was administered immediately after renal reperfusion. In CRS serum-exposed H9c2 cells, 1-MH reduced reactive oxygen species-associated fluorescence, malondialdehyde content, and intracellular Fe ²⁺ levels. Transcriptomic profiling showed that 1-MH suppressed inflammatory signaling, accompanied by changes in oxidative metabolism. Integration of these transcriptomic signatures with target prediction prioritized NFKB1/p105, while ensemble docking identified recurrent candidate interaction regions within p105. Cellular thermal shift assays showed a concentration-related increase in p105 thermal stability following 1-MH treatment. 1-MH increased p105 abundance while reducing total p50 abundance and nuclear p50 accumulation. p105 overexpression increased p50 abundance and the expression of inflammatory transcripts and proteins suppressed by 1-MH. These findings demonstrate that 1-MH attenuates early myocardial inflammation in CRS3 and reduces oxidative stress-related changes in CRS serum-exposed H9c2 cells. These functional results support modulation of the p105/p50 NF-κB axis and identify p105 as a molecular link between AKI-associated metabolic remodeling and myocardial inflammatory signaling.
SN - 1663-9812
ER -