Department of Pharmacology, Dalian Medical University, Dalian, China; Institute of Integrative Medicine, Dalian Medical University, Dalian, China.
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Department of Hepatobiliary and Pancreatic Surgery, Department of Liver Transplantation, Shulan (Hangzhou) Hospital, Hangzhou, China.
Redox Biol. 2022 Aug;54:102378. doi: 10.1016/j.redox.2022.102378. Epub 2022 Jun 24.
Peroxiredoxin 3 (PRDX3) acts as a master regulator of mitochondrial oxidative stress and exerts hepatoprotective effects, but the role of PRDX3 in liver fibrosis is not well understood. N-methyladenosine (m6A) is considered the most prevalent posttranscriptional modification of mRNA. This study aimed to elucidate the effect of PRDX3 on liver fibrosis and the potential mechanism through which the m6A modification regulates PRDX3. PRDX3 expression was found to be negatively correlated with liver fibrosis in both animal models and clinical specimens from patients. We performed adeno-associated virus 9 (AAV9)-PRDX3 knockdown and AAV9-PRDX3 HSC-specific overexpression in mice to clarify the role of PRDX3 in liver fibrosis. PRDX3 silencing exacerbated hepatic fibrogenesis and hepatic stellate cell (HSC) activation, whereas HSC-specific PRDX3 overexpression attenuated liver fibrosis. Mechanistically, PRDX3 suppressed HSC activation at least partially via the mitochondrial reactive oxygen species (ROS)/TGF-β1/Smad2/3 pathway. Furthermore, PRDX3 mRNA was modified by m6A and interacted with the m6A readers YTH domain family proteins 1-3 (YTHDF1-3), as evidenced by RNA pull-down/mass spectrometry. More importantly, PRDX3 expression was suppressed when YTHDF3, but not YTHDF1/2, was knocked down. Moreover, PRDX3 translation was directly regulated by YTHDF3 in an m6A-dependent manner and thereby affected its function in liver fibrosis. Collectively, the results indicate that PRDX3 is a crucial regulator of liver fibrosis and that targeting the YTHDF3/PRDX3 axis in HSCs may be a promising therapeutic approach for liver fibrosis.
过氧化物酶 3（PRDX3）作为线粒体氧化应激的主要调节剂，发挥着肝保护作用，但 PRDX3 在肝纤维化中的作用尚不清楚。N6-甲基腺苷（m6A）被认为是 mRNA 最普遍的转录后修饰。本研究旨在阐明 PRDX3 对肝纤维化的影响，以及 m6A 修饰调节 PRDX3 的潜在机制。在动物模型和患者的临床标本中均发现 PRDX3 的表达与肝纤维化呈负相关。我们在小鼠中进行了腺相关病毒 9（AAV9）-PRDX3 敲低和 AAV9-PRDX3 肝星状细胞（HSC）特异性过表达，以阐明 PRDX3 在肝纤维化中的作用。PRDX3 沉默加剧了肝纤维化和 HSC 激活，而 HSC 特异性 PRDX3 过表达则减轻了肝纤维化。在机制上，PRDX3 通过线粒体活性氧（ROS）/TGF-β1/Smad2/3 途径至少部分抑制 HSC 激活。此外，PRDX3 mRNA 被 m6A 修饰，并与 m6A 阅读器 YTH 结构域家族蛋白 1-3（YTHDF1-3）相互作用，这一点可以通过 RNA 下拉/质谱来证明。更重要的是，当敲低 YTHDF3 而不是 YTHDF1/2 时，PRDX3 的表达受到抑制。此外，PRDX3 的翻译受 YTHDF3 的 m6A 依赖性直接调控，从而影响其在肝纤维化中的功能。总之，这些结果表明 PRDX3 是肝纤维化的关键调节因子，靶向 HSCs 中的 YTHDF3/PRDX3 轴可能是肝纤维化的一种有前途的治疗方法。
