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<p>Acetaminophen (APAP)-induced acute liver injury (ALI) is a leading cause of acute liver failure, in which pyroptosis plays an important pathogenic role; however, the involvement of the long non-coding RNA MALAT1 remains unclear. Here, we investigated the role of MALAT1 in APAP-induced hepatocyte pyroptosis using THLE-2 cells and an ALI mouse model. MALAT1 expression was markedly upregulated following APAP exposure, whereas MALAT1 knockdown significantly reduced the expression of pyroptosis-related proteins (NLRP3, cleaved Caspase1, and GSDMD-N), decreased IL-1β and IL-18 release, and attenuated pyroptotic cell death. Mechanistically, MALAT1 directly interacted with metadherin (MTDH), thereby stabilizing Rac1 mRNA and enhancing Rac1 expression; overexpression of MTDH or Rac1 partially reversed the anti-pyroptotic effects of MALAT1 silencing. Importantly, Muniziqi Saifula (SFL) treatment suppressed the MALAT1/MTDH/Rac1 axis and alleviated APAP-induced hepatocyte pyroptosis both in vitro and in vivo. Collectively, these findings identify a MALAT1–MTDH–Rac1 signaling axis that promotes APAP-induced hepatocyte pyroptosis and suggest that SFL exerts hepatoprotective effects by targeting this pathway, providing potential therapeutic insight for drug-induced liver injury.</p>

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MALAT1 promotes acetaminophen-induced hepatocyte pyroptosis by stabilizing Rac1 through its interaction with MTDH and the hepatoprotective role of muniziqi saifula

  • 期刊论文

  • 发表日期：

    2026年2月14日

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  • Yilifanjiang Kuerban,
  • Aman Gul,
  • Zulipikaer Wusiman,
  • Shixia Huo,
  • Maimaitiyili Ruermaiti,
  • Atikanmu Wahefu,
  • Sikandaier Wushouer,
  • Mireguli Kamili,
  • Akenmujiang Aierken,
  • Zhijian Li,
  • Ainiwaer Talifu

摘要

Acetaminophen (APAP)-induced acute liver injury (ALI) is a leading cause of acute liver failure, in which pyroptosis plays an important pathogenic role; however, the involvement of the long non-coding RNA MALAT1 remains unclear. Here, we investigated the role of MALAT1 in APAP-induced hepatocyte pyroptosis using THLE-2 cells and an ALI mouse model. MALAT1 expression was markedly upregulated following APAP exposure, whereas MALAT1 knockdown significantly reduced the expression of pyroptosis-related proteins (NLRP3, cleaved Caspase1, and GSDMD-N), decreased IL-1β and IL-18 release, and attenuated pyroptotic cell death. Mechanistically, MALAT1 directly interacted with metadherin (MTDH), thereby stabilizing Rac1 mRNA and enhancing Rac1 expression; overexpression of MTDH or Rac1 partially reversed the anti-pyroptotic effects of MALAT1 silencing. Importantly, Muniziqi Saifula (SFL) treatment suppressed the MALAT1/MTDH/Rac1 axis and alleviated APAP-induced hepatocyte pyroptosis both in vitro and in vivo. Collectively, these findings identify a MALAT1–MTDH–Rac1 signaling axis that promotes APAP-induced hepatocyte pyroptosis and suggest that SFL exerts hepatoprotective effects by targeting this pathway, providing potential therapeutic insight for drug-induced liver injury.