2. Academic Validation
  3. Activin A exacerbates neonatal necrotizing enterocolitis via ALK4-mediated apoptosis and barrier disruption

Activin A exacerbates neonatal necrotizing enterocolitis via ALK4-mediated apoptosis and barrier disruption

  • Int Immunopharmacol. 2025 Aug 28:161:115043. doi: 10.1016/j.intimp.2025.115043.
Wenjing Ma 1,  Jiali Xie 1,  Lu Liu 1,  Xi Yuan 1,  Xiaoyan Yu 1,  Kai Chen 2,  Yue Li 3,  Wei Liu 1,  Xuemei Zhang 4,  Dapeng Chen 5,  Zhixin Song 6
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China.
  • 2 Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China; Department of Laboratory Medicine, Key Laboratory of Diagnostic Medicine, Chongqing Medical University, Chongqing 400016, China.
  • 3 Molecular Medicine and Cancer Research Center, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, China.
  • 4 Department of Laboratory Medicine, Key Laboratory of Diagnostic Medicine, Chongqing Medical University, Chongqing 400016, China.
  • 5 Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China. Electronic address: chendapeng@hospital.cqmu.edu.cn.
  • 6 Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Pediatric Metabolism and Inflammatory Diseases, Chongqing, China. Electronic address: songzhixin@hospital.cqmu.edu.cn.
PMID: 40494204 DOI: 10.1016/j.intimp.2025.115043
Abstract

Background: Necrotizing enterocolitis (NEC) is a life-threatening gastrointestinal disorder in neonates, yet the role of Activin A (ACV A) in NEC pathogenesis remains unclear.

Methods: NEC was induced in neonatal mice through hypoxia, hypothermia, LPS, and formula feeding. An in vitro intestinal epithelial injury model was established using LPS-stimulated IEC-6 cells. Recombinant Activin A (rActivin A) and neutralizing antibody (anti-Activin A) were used for intervention. Comprehensive evaluations were performed to assess intestinal injury, barrier function (ZO-1 / Occludin / Claudin-1), inflammation (IL-1β/IL-6), and Apoptosis through histopathology, ELISA, immunofluorescence, TUNEL, flow cytometry, and Western blotting. Specific inhibitors are utilized for reverse validation.

Results: Activin A expression was significantly upregulated in intestinal tissues of NEC mice. Exogenous rActivin A worsened NEC outcomes, including weight loss, mortality, histopathological damage, and reduced tight junction proteins (ZO-1, Occludin, Claudin-1). This was accompanied by increased pro-inflammatory cytokines (IL-1β, IL-6) and epithelial Apoptosis (Bax/Cleaved caspase-9 upregulation). Conversely, anti-Activin A reversed these effects. In vitro, Activin A enhanced LPS-induced IEC-6 Apoptosis, which was abrogated by ALK4 inhibition. Mechanistically, Activin A activated SMAD2/3 phosphorylation in an ALK4-dependent manner, without affecting NF-κB, ERK, or Akt pathways.

Conclusions: Activin A drives NEC progression through ALK4-Smad2/3-mediated Apoptosis and barrier disruption. Targeting the Activin A-ALK4 axis may offer novel therapeutic strategies for NEC.

Keywords

ALK4-Smad2/3; Activin A; Apoptosis; Barrier dysfunction; Necrotizing enterocolitis.

Figures
Products