Succinic Acid-Induced Macrophage Endocytosis Promotes Extracellular Vesicle-Based Integrin Beta1 Transfer Accelerating Fibroblast Activation and Sepsis-Associated Pulmonary Fibrosis

  • Adv Sci (Weinh). 2025 Sep 2:e07411. doi: 10.1002/advs.202507411.
Wenyu Yang  1  2 ,  Ri Tang  1  2 ,  Yang Zhou  1  2 ,  Jinquan Zhang  3 ,  Shuya Mei  1  2 ,  Yawen Peng  1  2 ,  Xi Huang  1  2 ,  Shunpeng Xing  1  2 ,  Yuan Gao  1  2 ,  Qiaoyi Xu  1  2 ,  Zhengyu He  1  2
Affiliations
  • 1. Department of Critical Care Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
  • 2. Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, 200127, China.
  • 3. Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China.
PMID: 40898357 DOI: 10.1002/advs.202507411
Abstract

Sepsis-associated pulmonary fibrosis (SAPF) is a life-threatening condition driven by persistent fibroblast activation and excessive extracellular matrix (ECM) deposition. While metabolic reprogramming, profibrotic extracellular vesicles (EVs), and Integrin activation are implicated in pulmonary fibrosis, their interplay remains unclear. This study reveals that succinic acid, a product of glycometabolic reprogramming, promotes macrophage-mediated endocytosis, driving the release of profibrotic EVs. These EVs transfer Integrin beta1 (ITGβ1) from macrophages to fibroblasts, activating fibroblasts and advancing SAPF. Through Single-cell RNA Sequencing (scRNA-seq), proteomics, immunofluorescence, and electron microscopy, the critical role of EV-mediated ITGβ1 transfer in macrophage-fibroblast communication is identified. Knockdown of ITGβ1 or Alix, a mediator of multivesicular bodies (MVBs) biogenesis, inhibited profibrotic EVs formation and alleviated SAPF. These findings highlight a novel mechanism in that the transfer ITGβ1 via EVs plays a critical role in macrophage-fibroblast communication, representing a novel mechanism underlying SAPF. Targeting EV-mediated ITGβ1 transfer can provide a promising therapeutic strategy to alleviate the progression of SAPF.

Keywords
extracellular vesicles; integrin β1; macrophage‐fibroblast communication; pulmonary fibrosis; sepsis.
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