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<p>Necrotizing enterocolitis (NEC) severely affects preterm infants with limited treatments. Although intestinal homeostasis dysfunction is considered a trigger for NEC, the key targets and mechanisms remain unclear. Using lipopolysaccharide-stimulated colonic epithelial cells and hypothermic hypoxia-induced NEC mice (both sexes), we demonstrate that the gut metabolite L-cystine alleviates intestinal inflammation by balancing Th17/Treg responses and inhibiting ferroptosis. Mechanistically, L-cystine directly targets KIF11 to suppress RC3H1 expression, blocking <i>IL-6</i> transcripts through transcriptional modifications, thereby inhibiting IL-6 secretion and ferroptosis. Conditioned medium from L-cystine-treated cells inactivates IL-6/STAT3 signaling, reducing pro-inflammatory cytokine release and restoring Th17/Treg balance. Notably, microbiota colonization from NEC preterm infants exacerbates intestinal damage, an effect mitigated by L-cystine and IL-6/STAT3 inhibition. Thus, L-cystine attenuates NEC by suppressing ferroptosis in epithelial cells, restoring immune homeostasis, and preserving intestinal barrier integrity. Targeting intestinal metabolites represents a promising prophylactic and therapeutic strategy for NEC, addressing unmet clinical needs in neonatal intestinal injury management.</p><p></p>

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L-cystine alleviates necrotizing enterocolitis by regulating ferroptosis and Th17 cell differentiation via the IL-6/STAT3 pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月29日

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  • Qin Zhu,
  • Yuyin Wang,
  • Yifan Zhou,
  • Xin Wu,
  • Hongyan Zai,
  • Yu Hu

摘要

Necrotizing enterocolitis (NEC) severely affects preterm infants with limited treatments. Although intestinal homeostasis dysfunction is considered a trigger for NEC, the key targets and mechanisms remain unclear. Using lipopolysaccharide-stimulated colonic epithelial cells and hypothermic hypoxia-induced NEC mice (both sexes), we demonstrate that the gut metabolite L-cystine alleviates intestinal inflammation by balancing Th17/Treg responses and inhibiting ferroptosis. Mechanistically, L-cystine directly targets KIF11 to suppress RC3H1 expression, blocking IL-6 transcripts through transcriptional modifications, thereby inhibiting IL-6 secretion and ferroptosis. Conditioned medium from L-cystine-treated cells inactivates IL-6/STAT3 signaling, reducing pro-inflammatory cytokine release and restoring Th17/Treg balance. Notably, microbiota colonization from NEC preterm infants exacerbates intestinal damage, an effect mitigated by L-cystine and IL-6/STAT3 inhibition. Thus, L-cystine attenuates NEC by suppressing ferroptosis in epithelial cells, restoring immune homeostasis, and preserving intestinal barrier integrity. Targeting intestinal metabolites represents a promising prophylactic and therapeutic strategy for NEC, addressing unmet clinical needs in neonatal intestinal injury management.