PDF(Pubmed)
Abstract：
Deoxynivalenol (DON) is a prevalent toxin causing severe liver damage through hepatocellular oxidative stress. However, the underlying mechanisms and effective therapeutic approaches remain unknown. Here, the unique role of the xenobiotic metabolism factor pregnane X receptor (PXR) in mediating DON-induced hepatocellular oxidative stress is investigated. Treatment with the PXR agonist 3-indole-propionic acid (IPA) alleviates DON-induced oxidative stress and liver injury both in vitro and in vivo. Mechanistically, it is discovered for the first time that PXR agonist IPA directly transactivates the m6A demethylase FTO expression, leading to site-specific demethylation and decreased abundance of YTHDC1-bound Malat1 lncRNA at single-nucleotide resolution. The diminished m6A modification of Malat1 lncRNA reduces its stability and augments antioxidant pathways governed by NRF2, consequently mitigating DON-induced liver injury. Furthermore, Malat1 knockout mice exhibit decreased DON-induced liver injury, emphasizing the role of Malat1 lncRNA in oxidative stress. Collectively, the findings establish that PXR-mediated m6A-dependent Malat1 lncRNA expression determines hepatocyte oxidative stress via m6A demethylase FTO, providing valuable insights into the potential mechanisms underlying DON-induced liver injury and offers potential therapeutic strategies for its treatment.
摘要：
脱氧雪腐镰刀菌烯醇（DON）是一种常见的毒素，可通过肝细胞氧化应激引起严重的肝损伤。然而,潜在的机制和有效的治疗方法仍然未知.这里,研究了外源性生物代谢因子孕烷X受体（PXR）在介导DON诱导的肝细胞氧化应激中的独特作用。用PXR激动剂3-吲哚-丙酸(IPA)处理可在体外和体内减轻DON诱导的氧化应激和肝损伤。机械上,首次发现PXR激动剂IPA直接反式激活m6A去甲基酶FTO的表达，导致位点特异性去甲基化，并降低单核苷酸分辨率下与YTHDC1结合的Malat1lncRNA的丰度。Malat1lncRNA的m6A修饰减少了其稳定性并增强了由NRF2控制的抗氧化途径，从而减轻了DON诱导的肝损伤。此外，Malat1基因敲除小鼠表现出减少DON诱导的肝损伤，强调Malat1lncRNA在氧化应激中的作用。总的来说，研究结果证实，PXR介导的m6A依赖性Malat1lncRNA表达通过m6A去甲基酶FTO决定肝细胞氧化应激，为DON诱导的肝损伤的潜在机制提供有价值的见解，并为其治疗提供潜在的治疗策略。
