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
  • 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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