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Peer-reviewedCC BY 4.0Frontiers in Immunology

Immunometabolic reprogramming: a working framework for disease development, endotype differentiation, and therapeutic considerations in pediatric asthma

  • Kaiwen Zheng1,2
  • Ran Ma1,2
  • Yingqian Zhang2,3,4
4 affiliations
  1. 1Graduate School, Hebei Medical University, Shijiazhuang
  2. 2Department No. 3 of Respiratory Medicine, Hebei Children’s Hospital, Shijiazhuang
  3. 3Hebei Provincial Clinical Research Center for Child Health and Disease, Hebei Children’s Hospital, Shijiazhuang
  4. 4Hebei Key Laboratory of Pediatric Allergy and Immunology, Hebei Children’s Hospital, Shijiazhuang
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Abstract

Background: Paediatric asthma exhibits marked clinical heterogeneity and cannot be simply considered the childhood counterpart of adult asthma. Early-life environmental exposures can reshape immune-cell metabolic programs and potentially drive long-lasting inflammatory phenotypes. Existing explanatory frameworks for paediatric asthma largely centre on Th2-related inflammation, epithelial-alarm signalling and neuro-immune crosstalk, while the contributions of immunometabolic processes to disease endotypes remain under-summarised.

Objective: This review collates available evidence regarding metabolic reprogramming in the pathogenesis of paediatric asthma and provides an integrated immunometabolic perspective on this condition.

Results: Summarized evidence covers immunometabolic changes across key airway-resident and infiltrating cell populations. Discussion addresses core paediatric-specific biological features, including early-life developmental windows, virus-related trained immunity, obese asthma, circadian-sleep interactions, neuro-metabolic-immune communication and metabolomics-based endotyping. The framework is organized around substrate competition rather than a glycolysis-versus-OXPHOS binary, because Tregs, M2-like macrophages and pathogenic ILC2s share lipid and amino-acid pools but exert opposing functions. From these observations emerges a testable “Metabolic Latching Model” of how early-life insults establish persistent inflammatory memory through metabolism–epigenetic coupling, with “latching” operationally defined by exposure removal and persistence beyond responding-cell turnover. Group 2 innate lymphoid cells (ILC2s) and the Treg-to-effector balance are placed at the centre of this framework. Three hypotheses are prioritised as feasible with current technology: H1 (monocyte glycolytic baseline predicting wheeze-to-asthma transition), H4 (metabolic intervention in obese asthma), and H6 (the HDAC2-GSH/butyrate axis in steroid sensitivity).

Conclusion: Current evidence suggests that immunometabolic reprogramming serves as one plausible contributing factor for the heterogeneity of paediatric asthma. This conceptual framework may bridge molecular metabolic findings and paediatric clinical contexts, and inform future mechanistic and clinical studies in this research area.

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Cite

BibTeXRIS
BibTeX
@article{zheng2026immunometabolic,
  title = {{Immunometabolic reprogramming: a working framework for disease development, endotype differentiation, and therapeutic considerations in pediatric asthma}},
  author = {Kaiwen Zheng and Ran Ma and Yingqian Zhang},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1999531},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1999531/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Immunometabolic reprogramming: a working framework for disease development, endotype differentiation, and therapeutic considerations in pediatric asthma
AU  - Kaiwen Zheng
AU  - Ran Ma
AU  - Yingqian Zhang
PY  - 2026
DA  - 2026/10/19
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1999531
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1999531/full
AB  - Background: Paediatric asthma exhibits marked clinical heterogeneity and cannot be simply considered the childhood counterpart of adult asthma. Early-life environmental exposures can reshape immune-cell metabolic programs and potentially drive long-lasting inflammatory phenotypes. Existing explanatory frameworks for paediatric asthma largely centre on Th2-related inflammation, epithelial-alarm signalling and neuro-immune crosstalk, while the contributions of immunometabolic processes to disease endotypes remain under-summarised.  Objective: This review collates available evidence regarding metabolic reprogramming in the pathogenesis of paediatric asthma and provides an integrated immunometabolic perspective on this condition.  Results: Summarized evidence covers immunometabolic changes across key airway-resident and infiltrating cell populations. Discussion addresses core paediatric-specific biological features, including early-life developmental windows, virus-related trained immunity, obese asthma, circadian-sleep interactions, neuro-metabolic-immune communication and metabolomics-based endotyping. The framework is organized around substrate competition rather than a glycolysis-versus-OXPHOS binary, because Tregs, M2-like macrophages and pathogenic ILC2s share lipid and amino-acid pools but exert opposing functions. From these observations emerges a testable “Metabolic Latching Model” of how early-life insults establish persistent inflammatory memory through metabolism–epigenetic coupling, with “latching” operationally defined by exposure removal and persistence beyond responding-cell turnover. Group 2 innate lymphoid cells (ILC2s) and the Treg-to-effector balance are placed at the centre of this framework. Three hypotheses are prioritised as feasible with current technology: H1 (monocyte glycolytic baseline predicting wheeze-to-asthma transition), H4 (metabolic intervention in obese asthma), and H6 (the HDAC2-GSH/butyrate axis in steroid sensitivity).  Conclusion: Current evidence suggests that immunometabolic reprogramming serves as one plausible contributing factor for the heterogeneity of paediatric asthma. This conceptual framework may bridge molecular metabolic findings and paediatric clinical contexts, and inform future mechanistic and clinical studies in this research area.
SN  - 1664-3224
ER  -