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<p>Preterm birth (PTB) is a principal contributor to neonatal morbidity, wherein inflammation and dysregulated cell death pathways are implicated as key drivers in its pathogenesis. However, the role of the RIPK1/RIPK3-MLKL signaling axis, a critical regulator of necroptosis and inflammatory responses, remains poorly characterized in the context of PTB. Here, we sought to elucidate the role of RIPK1-mediated activation of the RIPK3-MLKL pathway in placental inflammation and its involvement in PTB pathogenesis. In vitro experiments were conducted using TNF-α-stimulated HTR8/SVneo trophoblasts, while an LPS-induced murine model was employed to mimic inflammation-associated PTB. RIPK1 expression was modulated via shRNA-mediated knockdown or pharmacological inhibition with GSK2982772 and Nec-1. Molecular analyses included qPCR, Western blotting, ELISA, and the assessment of necroptosis via PI staining. We found that TNF-α and LPS significantly upregulated RIPK1 expression and activated the RIPK3-MLKL pathway in both the cellular and animal models. RIPK1 knockdown or pharmacological inhibition attenuated TNF-α-induced proinflammatory cytokine release (IL-1β, IL-6, TNF-α), uric acid accumulation, RIPK3-MLKL pathway activation, and necroptosis in trophoblasts at both 24 and 48 h. Notably, in vivo treatment with Nec-1 ameliorated LPS-induced placental damage. Collectively, our findings demonstrate that RIPK1 drives inflammation and necroptosis in PTB through RIPK3-MLKL activation, suggesting that targeting RIPK1 may represent a promising therapeutic strategy for inflammation-associated preterm labor.</p>

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Inhibition of RIPK1/RIPK3-MLKL inflammatory signaling pathway activation attenuates preterm birth

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月18日

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  • Xuexiang Bing,
  • Yongqing Wang,
  • Jiacui Zheng,
  • Guodong Gao,
  • Jinxiao Jiang,
  • Lanlan Liu,
  • Xue Zhang

摘要

Preterm birth (PTB) is a principal contributor to neonatal morbidity, wherein inflammation and dysregulated cell death pathways are implicated as key drivers in its pathogenesis. However, the role of the RIPK1/RIPK3-MLKL signaling axis, a critical regulator of necroptosis and inflammatory responses, remains poorly characterized in the context of PTB. Here, we sought to elucidate the role of RIPK1-mediated activation of the RIPK3-MLKL pathway in placental inflammation and its involvement in PTB pathogenesis. In vitro experiments were conducted using TNF-α-stimulated HTR8/SVneo trophoblasts, while an LPS-induced murine model was employed to mimic inflammation-associated PTB. RIPK1 expression was modulated via shRNA-mediated knockdown or pharmacological inhibition with GSK2982772 and Nec-1. Molecular analyses included qPCR, Western blotting, ELISA, and the assessment of necroptosis via PI staining. We found that TNF-α and LPS significantly upregulated RIPK1 expression and activated the RIPK3-MLKL pathway in both the cellular and animal models. RIPK1 knockdown or pharmacological inhibition attenuated TNF-α-induced proinflammatory cytokine release (IL-1β, IL-6, TNF-α), uric acid accumulation, RIPK3-MLKL pathway activation, and necroptosis in trophoblasts at both 24 and 48 h. Notably, in vivo treatment with Nec-1 ameliorated LPS-induced placental damage. Collectively, our findings demonstrate that RIPK1 drives inflammation and necroptosis in PTB through RIPK3-MLKL activation, suggesting that targeting RIPK1 may represent a promising therapeutic strategy for inflammation-associated preterm labor.