# Hydrogen activates ACOD1-itaconate pathway to ameliorate steroid-associated osteonecrosis.
> 水素がACOD1-イタコン酸経路を活性化してステロイド性骨壊死を軽減する


## Abstract

Using a glucocorticoid-induced steroid-associated osteonecrosis (SAON) mouse model, this study examined the effects of hydrogen-rich water (HRW) administered orally. HRW-treated animals showed reduced osteocyte apoptosis, restored trabecular bone architecture, elevated osteoblast counts and bone formation rates, and decreased osteoclast numbers and bone resorption. Serum lipid parameters—including LDL, triglycerides, and total cholesterol—were lowered, and lipid accumulation was diminished. HRW also promoted type H vessel formation and enhanced blood perfusion in bone tissue. Macrophage polarization shifted from the M1 to M2 phenotype, accompanied by suppression of TNF-α. RNA sequencing identified upregulation of ACOD1 mRNA and protein in bone tissue following HRW exposure. Supplementation with the itaconate derivative dimethyl itaconate reproduced these protective effects in a dose-dependent fashion, implicating the ACOD1-itaconate pathway as a central mediator. These results indicate that HRW exerts bone-protective effects in SAON through modulation of this metabolic-inflammatory axis.

### Mechanism

HRW upregulates ACOD1 expression in bone tissue, increasing itaconate production. Itaconate drives macrophage polarization from M1 to M2 and suppresses TNF-α, thereby reducing osteocyte apoptosis, lipid accumulation, and bone resorption while promoting bone formation and vascular perfusion.

## Bibliographic

- **Authors**: An Y, Zheng L, Zhang S, Zhang H, Zhang YJ, Shao H, et al.
- **Journal**: Biomaterials
- **Year**: 2025
- **PMID**: [40411985](https://pubmed.ncbi.nlm.nih.gov/40411985/)
- **DOI**: [10.1016/j.biomaterials.2025.123428](https://doi.org/10.1016/j.biomaterials.2025.123428)
- **Study type**: animal study
- **Delivery route**: hydrogen-rich water
- **Effect reported**: positive

## Delivery context

Hydrogen-rich water is a low-risk delivery route, but the achievable systemic hydrogen dose is bounded. For clinical applications, inhalation is the most efficient route; inhalation, however, carries explosion risk, and concentration matters (empirical LFL of 10% applies to inhalation environments; high-concentration devices are documented in the Consumer Affairs Agency accident database and are not recommended).

## Safety notes

Hydrogen-rich water is a low-risk delivery route, but the achievable systemic hydrogen dose is bounded. For clinical applications, inhalation is the most efficient route; inhalation, however, carries explosion risk, and concentration matters (empirical LFL of 10% applies to inhalation environments; high-concentration devices are documented in the Consumer Affairs Agency accident database and are not recommended).

See also:
- [Inhalation concentration and LFL / UFL](https://h2-papers.org/en/safety-notes/inhalation-concentration)
- [Consumer Affairs Agency accident cases](https://h2-papers.org/en/safety-notes/accident-cases)
- [Inhalation safety threshold lineage](https://h2-papers.org/en/safety-notes/lineage)

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> **Cite as**: H2 Papers — PMID 40411985. https://h2-papers.org/en/papers/40411985
> **Source**: PubMed PMID [40411985](https://pubmed.ncbi.nlm.nih.gov/40411985/)