METTL3 Modulates TXNIP Expression to Affect the Activation of NLRP3 Inflammasome in Hepatic Cells Under Oxygen-Glucose Deprivation/Reperfusion Injury

  • Inflammation. 2024 Jan 18. doi: 10.1007/s10753-023-01958-4.
Yong Zhang  1 ,  Jianrui Lv  1 ,  Jian Bai  2 ,  Xue Zhang  3 ,  Gang Wu  1 ,  Xiaoming Lei  1 ,  Wei Li  1 ,  Zhenni Zhang  4
Affiliations
  • 1. Anesthesia Department, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157, West 5th Road, Xi'an, Shaanxi Province, 710004, China.
  • 2. Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China.
  • 3. Department of General Practice, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
  • 4. Anesthesia Department, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157, West 5th Road, Xi'an, Shaanxi Province, 710004, China. [email protected].
PMID: 38236385 DOI: 10.1007/s10753-023-01958-4
Abstract

Hepatic ischemia-reperfusion (I/R) injury is still a major risk factor and unsolved problem in hepatic surgery. Methyltransferase-like 3 (METTL3), an important m6A-modified methylase, regulates inflammation and cellular stress response. In this study, we demonstrated the special role of METTL3 and its underlying mechanism in hepatic I/R injury. In the mouse model of hepatic I/R and in the oxygen-glucose deprivation and reoxygenation (OGD/R)-induced AML12 and NCTC 1469 cells, the expression of METTL3 was significantly upregulated. Inhibition of METTL3 in OGD/R-induced AML12 and NCTC 1469 cells both increased the cell viability, declined the cell Apoptosis, and decreased the Reactive Oxygen Species (ROS) and the release levels of interleukin-1β (IL-1β) and interleukin-18 (IL-18), diminishing NLRP3 and Caspase1-p20 expressions. Moreover, METTL3 positively modulated TXNIP expression in an m6A manner. TXNIP overexpression reversed the effects of METTL3 knockdown on OGD/R-induced injury in AML12 cells. Furthermore, inhibition of NLRP3 inflammasome activity contributed to the protective effects of TXNIP knockdown in OGD/R-induced AML12 cells. In conclusion, METTL3 knockdown alleviated OGD/R-induced hepatocyte injury, and the specific mechanism was associated with the inhibition of NLRP3 inflammasome activation, which was attributed to the reduction of TXNIP in an m6A-dependent manner.

Keywords
Hepatic ischemia/reperfusion injury; METTL3; NLRP3 inflammasome; TXNIP; m6A modification.
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