Adenosine dialdehyde regulates methylation metabolism and H3K4me3 modification to inhibit the NF-κB pathway and attenuate sepsis-induced inflammation and tissue injury

Zhao Yuting; Liu Xin; He Yulong; Wang Yujie; Pan Xue; Shao Xinyu; Wang Peng; Luo Xinyue; Li Xiaoli; Qiu Hongmei

doi:10.16016/j.2097-0927.202606028

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Adenosine dialdehyde regulates methylation metabolism and H3K4me3 modification to inhibit the NF-κB pathway and attenuate sepsis-induced inflammation and tissue injury

Basic Medicine | 更新时间：2026-10-01

- Adenosine dialdehyde regulates methylation metabolism and H3K4me3 modification to inhibit the NF-κB pathway and attenuate sepsis-induced inflammation and tissue injury
- Journal of Army Medical University Vol. 48, Issue 18, Pages: 2665-2676(2026)
- 作者机构：
  
  1.重庆医科大学药学院药理学系，重庆
  2.重庆高校生物化学与分子药理学重点实验室，重庆
  3.陆军军医大学（第三军医大学）第一附属医院临床医学研究中心，重庆
- 作者简介：
  
  Li Xiaoli，E-mail： lixiaoli@cqmu.edu.cn
  Qiu Hongmei，E-mail： qiuhongmei@cqmu.edu.cn
- 基金信息：
  
  the General Project of Natural Science Foundation of Chongqing(CSTB2025NSCQ-GPX1241)
- DOI：10.16016/j.2097-0927.202606028
  CLC： R342;R394.3;R631
- Received：05 June 2026，
  
  Revised：2026-07-09，
  
  Accepted：08 August 2026，
  
  Published：30 September 2026
- 稿件说明：
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赵雨婷，刘鑫，何宇龙，等.腺苷二醛调控甲基化代谢及H3K4me3修饰抑制NF-κB通路减轻脓毒症炎症与组织损伤［J］.陆军军医大学学报，2026，48（18）：2665-2676.DOI：10.16016/j.2097-0927.202606028.

Zhao Y T，Liu X，He Y L，et al.Adenosine dialdehyde regulates methylation metabolism and H3K4me3 modification to inhibit the NF-κB pathway and attenuate sepsis-induced inflammation and tissue injury［J］.J Army Med Univ，2026，48（18）：2665-2676.DOI：10.16016/j.2097-0927.202606028.
赵雨婷，刘鑫，何宇龙，等.腺苷二醛调控甲基化代谢及H3K4me3修饰抑制NF-κB通路减轻脓毒症炎症与组织损伤［J］.陆军军医大学学报，2026，48（18）：2665-2676.DOI：10.16016/j.2097-0927.202606028. DOI：

Zhao Y T，Liu X，He Y L，et al.Adenosine dialdehyde regulates methylation metabolism and H3K4me3 modification to inhibit the NF-κB pathway and attenuate sepsis-induced inflammation and tissue injury［J］.J Army Med Univ，2026，48（18）：2665-2676.DOI：10.16016/j.2097-0927.202606028. DOI：

摘要

目的

探讨腺苷二醛（adenosine dialdehyde，Adox）对脓毒症诱导的炎症反应及组织损伤的影响，并分析其对甲基化代谢稳态、H3K4me3修饰及NF-κB信号通路的调控作用。

方法

细胞实验：① CCK-8法检测Adox（2.5~40 μmol/L）处理小鼠单核巨噬细胞白血病细胞（RAW264.7）和人单核细胞白血病细胞系（THP-1）24 h后对细胞活力的影响，以筛选Adox的安全剂量范围。②ELISA检测不同浓度Adox（2.5、5、10、20、40 μmol/L）对脂多糖（lipopolysaccharide，LPS）诱导的炎症

因子释放的影响，并检测10 μmol/L Adox对100 ng/mL LPS不同刺激时间中巨噬细胞炎症因子释放的影响。③将RAW264.7和THP-1细胞分为：Medium组、LPS100组（100 ng/mL LPS刺激4 h）及LPS100+Adox组（10 μmol/L Adox和LPS共处理4 h），ELISA检测细胞上清TNF-α、IL-6、SAM及SAH水平；Western blot检测H3K4me3、SAHH及NF-κB/IκBα信号通路相关蛋白的表达；RT-qPCR检测TNF-α、IL-6 mRNA表达。动物实验：采用6~8周龄雄性C57BL/6J小鼠（体质量18~22 g），随机分为（

=6）：Sham（假手术）组、CLP［盲肠结扎穿孔（cecal ligation and puncture，CLP）脓毒症模型］组； CLP+Adox组（术前4 h腹腔注射2 mg/kg Adox后建立CLP模型），术后6 h取材。ELISA检测小鼠血清TNF-α、IL-6水平；HE染色及病理评分（0~12分）评价肺、脾组织损伤；Western blot检测肺、脾组织中H3K4me3、SAHH及NF-κB/IκBα信号通路相关蛋白的表达。

结果

细胞实验：CCK-8结果显示，Adox在2.5~40 μmol/L范围内对RAW264.7和THP-1细胞无明显毒性。ELISA结果表明，Adox可呈浓度依赖性和时间依赖性显著降低细胞中TNF-α和IL-6的释放水平（

0.01），10 μmol/L Adox在显著抑制炎症因子的同时对细胞活力无明显影响，用于后续实验。Adox处理后RAW264.7细胞上清中SAM水平降低，SAH水平升高，SAM/SAH比值下降（

0.01）。Western blot结果显示，Adox可显著降低炎症状态下RAW264.7和THP-1细胞中SAHH及H3K4me3蛋白表达水平（

0.01）并抑制NF-κB信号通路活化。动物实验：ELISA结果显示，Adox可显著降低CLP诱导的脓毒症小鼠血清TNF-α和IL-6水平（

0.01）。HE染色及病理评分显示，Adox可改善脓毒症小鼠肺、脾组织损伤。Western blot结果显示，Adox可显著降低CLP小鼠肺、脾组织中H3K4me3水平，并抑制NF-κB/IκBα信号通路活化。

结论

Adox可减轻脓毒症相关炎症反应及组织损伤，其机制可能与调控SAHH介导的SAM/SAH代谢、降低H3K4me3修饰水平以及抑制NF-κB信号通路活化有关。上述结果提示，靶向甲基化代谢及组蛋白甲基化修饰可能为脓毒症炎症干预提供新的治疗策略。

Abstract

Objective

To investigate the effects of adenosine dialdehyde (Adox) on sepsis-induced inflammatory response and tissue injury

and to analyze its regulatory roles in methylation metabolic homeostasis

H3K4me3 modification

and the NF-κB signaling pathway.

Methods

In vitro

experiments: ① Mouse mononuclear macrophage leukemia cells (RAW264.7) and human monocytic leukemia cells (THP-1) were subjected. CCK-8 assay was performed to determine the effects of Adox (2.5-40 μmol/L) on cell viability after 24 h of treatment in RAW264.7 and THP-1 cells to screen the safe dose range of Adox. ② ELISA was conducted to assess the

impact of various Adox concentrations (2.5

40 μmol/L) on lipopolysaccharide (LPS)-induced inflammatory cytokine release

and to examine the effect of 10 μmol/L Adox on the release of inflammatory cytokines at different time points following 100 ng/mL LPS stimulation. ③ RAW264.7 and THP-1 cells were divided into a Medium group

a LPS100 group (stimulated with 100 ng/mL LPS for 4 h)

and a LPS100+Adox group (co-treated with 10 μmol/L Adox and LPS for 4 h). ELISA was employed to measure TNF-α

IL-6

SAM and SAH levels in cell supernatants; Western blot was utilized to detect the protein expression of H3K4me3

SAHH and NF-κB/IκBα signaling pathway-related molecules; RT-qPCR was carried out to measure the mRNA expression of TNF-α and IL-6. Animal experiments: Male C57BL/6J mice (6 to 8 weeks old

weighing 18 to 22 g) were randomly assigned to a Sham group

a cecal ligation and puncture group (CLP

as a sepsis model)

and a CLP+Adox group (intraperitoneal injection of 2 mg/kg Adox administered 4 h prior to CLP surgery). Samples were collected 6 h after modeling. ELISA was used to detect serum TNF-α and IL-6 levels in mice; HE staining and pathological scoring (0-12) were utilized to evaluate lung and spleen tissue injury; Western blot was performed to detect the expression of H3K4me3

SAHH

and NF-κB/IκBα signaling pathway-related proteins in lung and spleen tissues.

Results

In vitro

experiments: CCK-8 results demonstrated that Adox had no obvious toxicity to RAW264.7 and THP-1 cells within the range of 2.5 to 40 μmol/L. ELISA revealed that Adox significantly reduced the released levels of TNF-α and IL-6 in a concentration- and time-dependent manner (

0.01). Notably

10 μmol/L Adox significantly suppressed inflammatory cytokines without affecting cell viability

and was therefore selected for subsequent experiments. Furthermore

Adox treatment decreased SAM levels

increased SAH levels

and reduced the SAM/SAH ratio in RAW264.7 cell supern

atants (

0.01). Western blot analysis demonstrated that Adox significantly downregulated the protein expression of SAHH and H3K4me3 in RAW264.7 and THP-1 cells under inflammatory conditions (

0.01)

and inhibited the activation of the NF-κB signaling pathway.

In vivo

experiments: ELISA results showed that Adox significantly decreased serum TNF-α and IL-6 levels in CLP-induced septic mice (

0.01). HE staining and pathological scoring demonstrated that Adox ameliorated lung and spleen injuries in septic mice. Western blot analysis indicated that Adox significantly reduced H3K4me3 levels and suppressed NF-κB/IκBα signaling pathway activation in the lung and spleen tissues of CLP mice.

Conclusion

Adox alleviates sepsis-related inflammatory response and tissue injury

and its mechanism may be related to the regulation of SAHH-mediated SAM/SAH metabolism

reduction of H3K4me3 modification levels

and inhibition of NF-κB signaling pathway activation. These findings suggest that targeting methylation metabolism and histone methylation modifications may provide a novel therapeutic strategy for intervening in sepsis-associated inflammation.

关键词

Keywords

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