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Peer-reviewedCC BY 4.0Advanced Science

DDX3x Regulates NINJ1 Transcription via Histone Lactylation in Sepsis Associated‐Acute Kidney Injury

  • Hongyu Liang1
  • Jihong Jiang2
  • Huanxin Yin3
  • Chunyan Liu1
  • Hongjun Huang1
  • Yan Luo1
  • Minmin Zhu4
  • Qiuyun Wang1
4 affiliations
  1. 1Department of Anesthesiology Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai China
  2. 2Department of Anesthesiology Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai China
  3. 3Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation School of Medicine Shanghai Fourth People's Hospital Tongji University Shanghai China
  4. 4Department of Anesthesiology Shanghai Pudong Hospital Fudan University Pudong Medical Center Shanghai China
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Abstract

Sepsis associated‐acute kidney injury (SA‐AKI), a severe complication of sepsis, is characterized by impaired tubular injury that can ultimately cause renal failure and patient mortality. Both histone and non‐histone lactylation and cellular PANoptosis have been implicated in the pathogenesis of SA‐AKI. In this study, we investigated how lactylation in histone H3 at lysines 9, 18, and 27 (H3K9/18/27la) modulates PANoptosis in SA‐AKI. Our findings revealed that lactate triggers PANoptosis by promoting H3K9/18/27la through the activation of Ninjurin‐1 (NINJ1) gene transcription in SA‐AKI. Notably, NINJ1, a membrane protein, is also lactylated at residues K111 (K111la) and K114 (K114la) in lipopolysaccharides (LPS)‐induced HK‐2 cells. NINJ1‐K111la mediates plasma membrane localization, thereby promoting cell death. Notably, we identified DEAD (Asp‐Glu‐Ala‐Asp)‐box helicase 3x (DDX3x), a previously unreported delactylase capable of regulating H3K9/18/27la levels, which influences NINJ1 transcription and PANoptosis. Furthermore, we developed Odetiglucan (Ode), a novel agonist targeting DDX3x delactylase function. Application of Ode in cecum ligation and puncture (CLP) mice or LPS‐induced HK‐2 cells significantly reduced H3K9/18/27la levels, inhibited NINJ1 transcription and PANoptosis, and alleviated SA‐AKI progression. In summary, DDX3x, function as a delactylase, regulates PANoptosis by influencing H3K9/18/27la. Thus, enhancing the delactylase activity of DDX3x may represent a potential therapeutic strategy for SA‐AKI.

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Cite

BibTeXRIS
BibTeX
@article{liang2026ddx3x,
  title = {{DDX3x Regulates NINJ1 Transcription via Histone Lactylation in Sepsis Associated‐Acute Kidney Injury}},
  author = {Hongyu Liang and Jihong Jiang and Huanxin Yin and Chunyan Liu and Hongjun Huang and Yan Luo and Minmin Zhu and Qiuyun Wang},
  journal = {Advanced Science},
  year = {2026},
  month = aug,
  doi = {10.1002/advs.76979},
  url = {https://doi.org/10.1002/advs.76979},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - DDX3x Regulates NINJ1 Transcription via Histone Lactylation in Sepsis Associated‐Acute Kidney Injury
AU  - Hongyu Liang
AU  - Jihong Jiang
AU  - Huanxin Yin
AU  - Chunyan Liu
AU  - Hongjun Huang
AU  - Yan Luo
AU  - Minmin Zhu
AU  - Qiuyun Wang
PY  - 2026
DA  - 2026/08/17
JO  - Advanced Science
DO  - 10.1002/advs.76979
UR  - https://doi.org/10.1002/advs.76979
AB  - Sepsis associated‐acute kidney injury (SA‐AKI), a severe complication of sepsis, is characterized by impaired tubular injury that can ultimately cause renal failure and patient mortality. Both histone and non‐histone lactylation and cellular PANoptosis have been implicated in the pathogenesis of SA‐AKI. In this study, we investigated how lactylation in histone H3 at lysines 9, 18, and 27 (H3K9/18/27la) modulates PANoptosis in SA‐AKI. Our findings revealed that lactate triggers PANoptosis by promoting H3K9/18/27la through the activation of Ninjurin‐1 (NINJ1) gene transcription in SA‐AKI. Notably, NINJ1, a membrane protein, is also lactylated at residues K111 (K111la) and K114 (K114la) in lipopolysaccharides (LPS)‐induced HK‐2 cells. NINJ1‐K111la mediates plasma membrane localization, thereby promoting cell death. Notably, we identified DEAD (Asp‐Glu‐Ala‐Asp)‐box helicase 3x (DDX3x), a previously unreported delactylase capable of regulating H3K9/18/27la levels, which influences NINJ1 transcription and PANoptosis. Furthermore, we developed Odetiglucan (Ode), a novel agonist targeting DDX3x delactylase function. Application of Ode in cecum ligation and puncture (CLP) mice or LPS‐induced HK‐2 cells significantly reduced H3K9/18/27la levels, inhibited NINJ1 transcription and PANoptosis, and alleviated SA‐AKI progression. In summary, DDX3x, function as a delactylase, regulates PANoptosis by influencing H3K9/18/27la. Thus, enhancing the delactylase activity of DDX3x may represent a potential therapeutic strategy for SA‐AKI.
SN  - 2198-3844
ER  -