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A neutrophil-intrinsic CKLF1–PKM2 axis drives glycolytic flux for de novo DAG synthesis and pro-inflammatory ROS production

Cell Death & Differentiation (2026) Cite this article

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Abstract

Reactive oxygen species (ROS) burst and subsequent recruitment to the ischemic brain characterize neutrophil activation in the hyperacute phase of ischemic stroke, yet the underlying metabolic drivers remain elusive. Here, we report that neutrophil-intrinsic chemokine-like factor 1 (CKLF1) acts as a key immunometabolic regulator following stroke. CKLF1 was rapidly upregulated in neutrophils within 6 h post-ischemia in both humans and mice. Mechanistically, CKLF1 bound directly to the tetrameric form of pyruvate kinase M2 (PKM2), enhancing glycolytic flux and diverting intermediates toward de novo diacylglycerol (DAG) synthesis. This rewiring promoted protein kinase C–dependent phosphorylation of p47‑phox and assembly of NADPH oxidase, driving ROS production that reinforced neutrophil recruitment and adhesion via αMβ2 integrin. Genetic deletion of neutrophil CKLF1 attenuated neutrophil recruitment and improved functional recovery. Leveraging this mechanism, we developed a neutrophil-targeted nanotherapeutic using engineered outer membrane vesicles from E. coli W3110 to deliver a stapled CKLF1-derived peptide (C19) that disrupts CKLF1–PKM2 binding. This intervention suppressed glycolysis-driven ROS, reduced neutrophil recruitment and αMβ2 expression, and provided robust neuroprotection. Our findings reveal a CKLF1-PKM2-DAG axis that directs metabolic reprogramming and neutrophil pathogenicity in stroke, offering a novel target for immunometabolic therapy.

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Fig. 1: Neutrophil CKLF1 is upregulated early after ischemic stroke and promotes ROS production.
The alternative text for this image may have been generated using AI.
Fig. 2: Neutrophil CKLF1 promotes ROS production via aerobic glycolysis–driven NADPH oxidase activation.
The alternative text for this image may have been generated using AI.
Fig. 3: CKLF1 enhances glycolysis to promote de novo synthesis of DAG in neutrophils.
The alternative text for this image may have been generated using AI.
Fig. 4: CKLF1 binds PKM2 tetramers to promote NADPH oxidase-dependent ROS production.
The alternative text for this image may have been generated using AI.
Fig. 5: Neutrophil CKLF1 governs recruitment to the ischemic vasculature and promotes vascular inflammation.
The alternative text for this image may have been generated using AI.
Fig. 6: Neutrophil Cklf1 knockout attenuates brain infarction and promotes functional recovery after stroke in male and female mice.
The alternative text for this image may have been generated using AI.
Fig. 7: Engineered OMVs delivering stabilized CKLF1-derived peptide C19 attenuate neutrophil metabolic dysfunction by competing with endogenous CKLF1 for PKM2 tetramer binding.
The alternative text for this image may have been generated using AI.
Fig. 8: CKLF1 promotes neutrophil recruitment by binding PKM2 to enhance glycolysis-driven DAG synthesis and ROS production.
The alternative text for this image may have been generated using AI.

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Data availability

Full uncropped western blots are available in the Supplementary Material. The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Funding

National Natural Science Foundation of China (U2202214, U21A20410, 82374060, 82130109). CAMS Innovation Fund for Medical Sciences (CIFMS) (2025-I2M- XHXX-099). Central Government Guidance Funds for Local Science and Technology Development Projects of Xinjiang Uygur Autonomous Region (ZYYD2026QY05) Key project of Xinjiang Natural Science Foundation (2022D01D50).

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  1. These authors contributed equally: Yuan Ruan, Pinglong Fan.

Authors and Affiliations

  1. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China

    Yuan Ruan, Pinglong Fan, Shanhe Qu, Kaichao Hu, Tianyi Zhang, Shifeng Chu, Zhao Zhang & Naihong Chen

  2. Tianjin University of Traditional Chinese Medicine, Tianjin, P. R. China

    Yuan Ruan & Naihong Chen

  3. Xinjiang Institute of Materia Medica, Urumqi, China

    Ruifang Zheng & Shifeng Chu

  4. Beijing hospital of integrated traditional Chinese and western medicine, Beijing, P. R. China

    Xiaolei Wu

  5. National International Joint Research Center for Molecular Chinese Medicine, Shanxi University of Chinese Medicine, Taiyuan, China

    Wen bin He & Zhao Zhang

  6. Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Hongshuo Sun & Zhongping Feng

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  1. Yuan Ruan
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Contributions

Conceptualization: NHC, SFC, ZZ. Methodology: YR, PLF, SFC, ZZ. Investigation: YR, PLF, RFZ, XLW, SHQ, KCH, TYZ. Visualization: YR, PLF, SFC, ZZ. Funding acquisition: SFC, ZZ, NHC. Project administration: NHC. Writing—original draft: YR, SFC, WBH. Writing—review & editing: SFC, ZZ, NHC, HSS, ZPF.

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Correspondence to Shifeng Chu, Zhao Zhang or Naihong Chen.

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All methods were performed in accordance with the relevant guidelines and regulations. All animal experimental procedures in this study were conducted in accordance with the ARRIVE guidelines and were approved by the Laboratory Animal Ethics Committee of the Chinese Academy of Medical Sciences and Peking Union Medical College (Ethics Approval No.: IMM-S-25-0320) prior to study initiation. This study involving human subjects was approved in advance by the Institutional Review Board (IRB) of Beijing Hospital of Integrated Traditional Chinese and Western Medicine (Ethics Approval No.: ZXYEC-KT-2025-45-P01). All human-related procedures were conducted in accordance with the Declaration of Helsinki and relevant ethical guidelines. Prior to the initiation of the study, written informed consent was obtained from all participants or their legally authorized representatives, who voluntarily participated after fully understanding the study objectives, procedures, potential risks, and anticipated benefits. Additional written informed consent was obtained from all participants for the publication of any identifiable images related to this manuscript.

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Ruan, Y., Fan, P., Zheng, R. et al. A neutrophil-intrinsic CKLF1–PKM2 axis drives glycolytic flux for de novo DAG synthesis and pro-inflammatory ROS production. Cell Death Differ (2026). https://doi.org/10.1038/s41418-026-01754-1

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