---
title: "Hyperglycemia worsens sepsis-associated acute lung injury via NPM3‑ACSL1 pathway–mediated ferropto"
id: "pubmed-42616601"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42616601"
content_type: "clinical_feed_article"
specialty: "Critical Care"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42616601/"
doi: "10.3724/abbs.2026149"
published_at: "2026-08-19T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Hyperglycemia worsens sepsis-associated acute lung injury via NPM3‑ACSL1 pathway–mediated ferropto
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42616601
- **Specialty:** [Critical Care](https://medichelpline.com/clinical-feed/critical-care.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42616601/)
- **DOI:** [10.3724/abbs.2026149](https://doi.org/10.3724%2Fabbs.2026149)
- **Published At:** 2026-08-19T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- Hyperglycemia (diabetes) is associated with poorer outcomes in septic patients and specifically aggravates **acute lung injury** (ALI) in sepsis, but the molecular mechanisms were previously unclear. - The study used both **in vivo** and **in vitro** models to investigate how elevated glucose promotes ALI and increases mortality during sepsis. - High expression of **NPM3** was identified as an upstream mediator that increases levels of the histone modification **H3K18la** and enhances H3K18la binding at the **ACSL1** promoter. - Upregulated **ACSL1** and its abnormal subcellular organelle localization in macrophages disturbed lipid metabolism, which precipitated **ferroptosis** in these immune cells. - Enhanced macrophage ferroptosis via the **NPM3‑H3K18la‑ACSL1** axis is a key mechanism by which hyperglycemia accelerates sepsis-associated ALI. - Pharmacologic or genetic inhibition targeting components of this axis suppressed hyperglycemia-induced ferroptosis in macrophages and reduced ALI severity and mortality in septic mice. - The authors propose that targeting the **NPM3‑H3K18la‑ACSL1** pathway could be a promising therapeutic strategy for hyperglycaemic or diabetic patients with sepsis-associated ALI. - Keywords emphasized by the source include **ACSL1**, **NPM3**, diabetes/hyperglycemia, **ferroptosis**, and sepsis.
## Clinical Analysis & Structured Key Points
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Online ahead of print. # Diabetes mellitus aggravates sepsis-induced lung injury by triggering NPM3-ACSL1 pathway-mediated ferroptosis [Zhuang Yu](https://pubmed.ncbi.nlm.nih.gov/?term=Yu+Z&cauthor_id=42616601)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42616601/#full-view-affiliation-1 "Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."), [Hongjiao Xu](https://pubmed.ncbi.nlm.nih.gov/?term=Xu+H&cauthor_id=42616601)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42616601/#full-view-affiliation-1 "Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."), [Yanlin Han](https://pubmed.ncbi.nlm.nih.gov/?term=Han+Y&cauthor_id=42616601)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42616601/#full-view-affiliation-2 "Department of Anesthesiology, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225009, China."), [Yu Zhou](https://pubmed.ncbi.nlm.nih.gov/?term=Zhou+Y&cauthor_id=42616601)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42616601/#full-view-affiliation-1 "Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."), [Jun Zhu](https://pubmed.ncbi.nlm.nih.gov/?term=Zhu+J&cauthor_id=42616601)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42616601/#full-view-affiliation-1 "Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."), [Haoran Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+H&cauthor_id=42616601)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42616601/#full-view-affiliation-1 "Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."), [Jihong Jiang](https://pubmed.ncbi.nlm.nih.gov/?term=Jiang+J&cauthor_id=42616601)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42616601/#full-view-affiliation-1 "Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."), [Jinbao Li](https://pubmed.ncbi.nlm.nih.gov/?term=Li+J&cauthor_id=42616601)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42616601/#full-view-affiliation-1 "Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."), [Minmin Zhu](https://pubmed.ncbi.nlm.nih.gov/?term=Zhu+M&cauthor_id=42616601)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42616601/#full-view-affiliation-1 "Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42616601/#full-view-affiliation-3 "Department of Anesthesiology, Shanghai Pudong Hospital; Fudan University Pudong Medical Center, Shanghai 201399, China.") Affiliations Expand ### Affiliations * 1 Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China. * 2 Department of Anesthesiology, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225009, China. * 3 Department of Anesthesiology, Shanghai Pudong Hospital; Fudan University Pudong Medical Center, Shanghai 201399, China. * PMID: **42616601** * DOI: [ 10.3724/abbs.2026149 ](https://doi.org/10.3724/abbs.2026149) Item in Clipboard # Diabetes mellitus aggravates sepsis-induced lung injury by triggering NPM3-ACSL1 pathway-mediated ferroptosis Zhuang Yu et al. Acta Biochim Biophys Sin (Shanghai). 2026. Show details Display options Display options Format Abstract PubMed PMID Acta Biochim Biophys Sin (Shanghai) Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Acta+Biochim+Biophys+Sin+%28Shanghai%29%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Acta+Biochim+Biophys+Sin+%28Shanghai%29%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42616601/) . 2026 Aug 19. doi: 10.3724/abbs.2026149. Online ahead of print. ### Authors [Zhuang Yu](https://pubmed.ncbi.nlm.nih.gov/?term=Yu+Z&cauthor_id=42616601)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42616601/#short-view-affiliation-1 "Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."), [Hongjiao Xu](https://pubmed.ncbi.nlm.nih.gov/?term=Xu+H&cauthor_id=42616601)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42616601/#short-view-affiliation-1 "Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."), [Yanlin Han](https://pubmed.ncbi.nlm.nih.gov/?term=Han+Y&cauthor_id=42616601)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42616601/#short-view-affiliation-2 "Department of Anesthesiology, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225009, China."), [Yu Zhou](https://pubmed.ncbi.nlm.nih.gov/?term=Zhou+Y&cauthor_id=42616601)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42616601/#short-view-affiliation-1 "Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."), [Jun Zhu](https://pubmed.ncbi.nlm.nih.gov/?term=Zhu+J&cauthor_id=42616601)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42616601/#short-view-affiliation-1 "Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."), [Haoran Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+H&cauthor_id=42616601)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42616601/#short-view-affiliation-1 "Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."), [Jihong Jiang](https://pubmed.ncbi.nlm.nih.gov/?term=Jiang+J&cauthor_id=42616601)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42616601/#short-view-affiliation-1 "Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."), [Jinbao Li](https://pubmed.ncbi.nlm.nih.gov/?term=Li+J&cauthor_id=42616601)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42616601/#short-view-affiliation-1 "Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China."), [Minmin Zhu](https://pubmed.ncbi.nlm.nih.gov/?term=Zhu+M&cauthor_id=42616601)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42616601/#short-view-affiliation-1 "Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42616601/#short-view-affiliation-3 "Department of Anesthesiology, Shanghai Pudong Hospital; Fudan University Pudong Medical Center, Shanghai 201399, China.") ### Affiliations * 1 Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China. * 2 Department of Anesthesiology, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225009, China. * 3 Department of Anesthesiology, Shanghai Pudong Hospital; Fudan University Pudong Medical Center, Shanghai 201399, China. * PMID: **42616601** * DOI: [ 10.3724/abbs.2026149 ](https://doi.org/10.3724/abbs.2026149) Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID ## Abstract Hyperglycemia is a poor prognostic factor in critically ill septic patients with diabetes. Acute lung injury (ALI) resulting from hyperglycemia combined with sepsis remains an urgent clinical challenge. However, the mechanisms by which hyperglycemia contributes to sepsis-associated ALI remain unclear. In this study, we investigate the molecular mechanisms through which hyperglycemia accelerates ALI and mortality in sepsis using _in vivo_ and _in vitro_ models. High NPM3 expression not only mediates H3K18la levels but also promotes its binding to the _ACSL1_ promoter. Elevated ACSL1 expression and abnormal subcellular organelle localization disrupt lipid metabolism in macrophages, ultimately leading to ferroptosis. Our findings indicate that hyperglycemia enhances ferroptosis via the NPM3-H3K18la-ACSL1 axis in macrophages during sepsis-associated ALI. Targeted inhibition of this axis effectively suppresses hyperglycemia-induced ferroptosis in macrophages and reduces ALI and mortality in septic mice. Thus, targeting the NPM3-H3K18la-ACSL1 axis represents a promising therapeutic strategy for hyperglycemic/diabetic patients with sepsis-associated ALI. **Keywords:** ACSL1; NPM3; diabetes/hyperglycemia; ferroptosis; sepsis. 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