ATF4-histone 2-hydroxyisobutyrylation feedback loop drives sepsis-induced inflammation

  • Br J Pharmacol. 2026 Jul 13. doi: 10.1111/bph.70554.
Liang Zhang  1  2 ,  Yongling Lu  3 ,  Hongmei Qiu  1  2 ,  Xinhui Shi  1  2 ,  Feng Cao  4 ,  Ting Yang  1  2 ,  Sijia Liu  1  2 ,  Qian Chen  3 ,  Qingsong Jiang  1  2 ,  Lin Xia  3 ,  Wenjun Li  5 ,  Junxia Yang  1  2 ,  Jiang Zheng  3 ,  Xin Liu  3 ,  Xiaoli Li  1  2 ,  Hong Zhou  6
Affiliations
  • 1. Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing, China.
  • 2. Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing, Chongqing, China.
  • 3. Medical Research Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
  • 4. Department of Emergency and Critical Care, Shanghai Changzheng Hospital of Naval Medical University, Shanghai, China.
  • 5. Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 6. Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China.
PMID: 42442942 DOI: 10.1111/bph.70554
Abstract

Background and purpose: The role and mechanisms of lysine 2-hydroxyisobutyrylation (Khib) in the acute inflammatory phase of Sepsis remain unclear. We investigated the function and underlying mechanisms of histone H4 lysine 5 2-hydroxyisobutyrylation (H4K5-hib) in sepsis-induced inflammation in vivo and in vitro.

Experimental approach: Acute Sepsis was induced by caecal ligation and puncture (CLP) in mice, and inflammatory responses were modelled in lipopolysaccharide (LPS)-stimulated Macrophages. CUT&Tag-seq was used to identify genomic targets associated with H4K5-hib and activating transcription factor 4 (ATF4). Immunofluorescence, Western blotting, qPCR, dual-luciferase assays, and ELISA were performed to investigate the underlying mechanisms.

Key results: H4K5-hib levels were increased in Macrophages during the acute inflammatory phase of Sepsis. LPS stimulation enhanced H4K5-hib enrichment at the ATF4 promoter, thereby promoting ATF4 transcription. Inhibition of EP300-mediated 2-hydroxyisobutyrylation or mutation of H4K5 abolished ATF4 activation. Increased H4K5-hib activated the ATF4/NLRP3 signalling axis, promoting inflammasome assembly and amplifying inflammatory responses. ATF4 directly bound to the EP300 promoter and enhanced its transcription, forming a positive feedback loop that further increased H4K5-hib levels. In CLP-induced Sepsis, pharmacological inhibition of EP300 or ATF4 reduced H4K5-hib levels and suppressed NLRP3 inflammasome activation.

Conclusion and implications: These findings reveal a previously unrecognized epigenetic mechanism underlying sepsis-induced inflammation and identify the EP300/ATF4/H4K5-hib positive feedback loop as a potential therapeutic target for Sepsis.

Keywords
ATF4; H4K5‐hib; NLRP3; histone 2‐hydroxyisobutyrylation; sepsis.
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