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<p>The ameliorative effects of heparin on acute pancreatitis (AP) have received widespread attention. NLRP3 inflammasome-dependent pyroptosis has been reported to be a key factor contributing to AP development. However, it remains unclear whether heparin alleviates AP by modulating NLRP3 inflammasome-dependent pyroptosis. An AP model was established in vivo and in vitro using Sprague Dawley rats and AR42J cells. TUNEL and propidium iodide staining assessed cell death. Cellular pyroptosis was observed under a microscope. Intermolecular interactions were verified using Co-IP and RIP assays. The m6A level of KAT2B was assessed by MeRIP. Levels of pro-inflammatory factors were determined using ELISA. Our results showed that heparin attenuated AP in vivo by inhibiting NLRP3-mediated pyroptosis. VIRMA expression was increased in AP. Meanwhile, overexpression of VIRMA reversed the alleviating effect of heparin on cellular pyroptosis. <i>KAT2B</i> knockdown counteracted the promotion of pyroptosis by VIRMA. Mechanically, VIRMA promoted KAT2B mRNA stability in an m6A–ELAVL1–dependent manner, whereas KAT2B upregulation further promoted NLRP3 acetylation at K694. The wild-type NLRP3 reversed the inhibitory of heparin on pyroptosis, and KAT2B amplified this regulatory effect. Taken together, heparin prevented cellular pyroptosis by inhibiting the VIRMA-mediated m6A modification of KAT2B, which in turn inhibited NLRP3 acetylation at K694, ultimately attenuating AP.</p>

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Heparin inhibits NLRP3-dependent pyroptosis in acute pancreatitis

  • 期刊论文

  • 发表日期：

    2026年3月19日

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  • Guanxiu Tang,
  • Wangjun Yan,
  • Xulin Li,
  • Xuan Zhang,
  • Di Wu,
  • Shangping Zhao

摘要

The ameliorative effects of heparin on acute pancreatitis (AP) have received widespread attention. NLRP3 inflammasome-dependent pyroptosis has been reported to be a key factor contributing to AP development. However, it remains unclear whether heparin alleviates AP by modulating NLRP3 inflammasome-dependent pyroptosis. An AP model was established in vivo and in vitro using Sprague Dawley rats and AR42J cells. TUNEL and propidium iodide staining assessed cell death. Cellular pyroptosis was observed under a microscope. Intermolecular interactions were verified using Co-IP and RIP assays. The m6A level of KAT2B was assessed by MeRIP. Levels of pro-inflammatory factors were determined using ELISA. Our results showed that heparin attenuated AP in vivo by inhibiting NLRP3-mediated pyroptosis. VIRMA expression was increased in AP. Meanwhile, overexpression of VIRMA reversed the alleviating effect of heparin on cellular pyroptosis. KAT2B knockdown counteracted the promotion of pyroptosis by VIRMA. Mechanically, VIRMA promoted KAT2B mRNA stability in an m6A–ELAVL1–dependent manner, whereas KAT2B upregulation further promoted NLRP3 acetylation at K694. The wild-type NLRP3 reversed the inhibitory of heparin on pyroptosis, and KAT2B amplified this regulatory effect. Taken together, heparin prevented cellular pyroptosis by inhibiting the VIRMA-mediated m6A modification of KAT2B, which in turn inhibited NLRP3 acetylation at K694, ultimately attenuating AP.