2. Academic Validation
  3. NEDD4 lactylation promotes APAP induced liver injury through Caspase11 dependent non-canonical pyroptosis

NEDD4 lactylation promotes APAP induced liver injury through Caspase11 dependent non-canonical pyroptosis

  • Int J Biol Sci. 2024 Feb 4;20(4):1413-1435. doi: 10.7150/ijbs.91284.
Qinglin Li 1 2 3,  Fengping Zhang 1 2,  Hai Wang 1 2,  Yingmu Tong 2 4,  Yunong Fu 1 2,  Kunjin Wu 2 5,  Jing Li 2 5,  Cong Wang 1 2,  Zi Wang 1 2,  Yifan Jia 2 6,  Rui Chen 1 2,  Yang Wu 1 2,  Ruixia Cui 1 2,  Yi Wu 7,  Yun Qi 8,  Kai Qu 2 5,  Chang Liu 2 5,  Jingyao Zhang 2 9
Affiliations

Affiliations

  • 1 Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi 710061, People's Republic of China.
  • 2 Key Laboratory of Surgical Critical Care and Life Support (Xi'an Jiaotong University), Ministry of Education, People's Republic of China.
  • 3 Department of Vascular Surgery, Xiangya Hospital, Central South University, Changsha, People's Republic of China.
  • 4 Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi 710061, People's Republic of China.
  • 5 Department of Hepatobiliary Surgery and Liver Transplantation, The Second Affiliated Hospital of Xi'an Jiaotong University, People's Republic of China.
  • 6 Department of Vascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi 710061, People's Republic of China.
  • 7 MOE Key Laboratory of Environment and Genes Related to Diseases, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an Shaanxi 710061, People's Republic of China.
  • 8 Department of Ophthalmology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi 710061, People's Republic of China.
  • 9 Department of SICU, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi 710061, People's Republic of China.
PMID: 38385085 DOI: 10.7150/ijbs.91284
Abstract

Caspase-11 detection of intracellular lipopolysaccharide mediates non-canonical Pyroptosis, which could result in inflammatory damage and organ lesions in various diseases such as sepsis. Our research found that lactate from the microenvironment of acetaminophen-induced acute liver injury increased Caspase-11 levels, enhanced gasdermin D activation and accelerated macrophage Pyroptosis, which lead to exacerbation of liver injury. Further experiments unveiled that lactate inhibits Caspase-11 ubiquitination by reducing its binding to NEDD4, a negative regulator of Caspase-11. We also identified that lactates regulated NEDD4 K33 lactylation, which inhibits protein interactions between Caspase-11 and NEDD4. Moreover, restraining lactylation reduces non-canonical Pyroptosis in macrophages and ameliorates liver injury. Our work links lactate to the exquisite regulation of the non-canonical inflammasome, and provides a basis for targeting lactylation signaling to combat Caspase-11-mediated non-canonical Pyroptosis and acetaminophen-induced liver injury.

Keywords

NEDD4.; caspase-11; lactate; lactylation; non-canonical pyroptosis.

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