FSTL1 aggravates LPS-induced liver injury through the NLRP3-CASP1-GSDMD and BAX-CASP3-GSDME pyroptosis pathways
Abstract
IntroductionHepatocellular pyroptosis and its proinflammatory effects critically contribute to the pathology of acute liver injury. FSTL1, a secreted glycoprotein, has been implicated in regulating multiple cell death pathways and promoting inflammatory disease progression. However, the regulatory mechanisms of FSTL1-mediated hepatocellular pyroptosis in sepsis-induced liver injury remain poorly understood. This study aimed to investigate the role of FSTL1 in hepatocyte pyroptosis during sepsis and evaluate its therapeutic potential.MethodsSeptic liver injury was induced by intraperitoneal LPS injection in mice. Hepatocyte-specific FSTL1 knockdown was achieved via AAV-mediated gene silencing prior to LPS challenge. Serum and liver tissues were collected at designated time points. We measured serum FSTL1, liver function markers (AST, ALT), evaluated histopathological changes, ROS production, pyroptosis pathway activation (NLRP3-CASP1-GSDMD and BAX-CASP3-GSDME), hepatic inflammation, and survival rates.ResultsSerum FSTL1 was significantly elevated and positively correlated with liver injury severity. Hepatic FSTL1 expression progressively increased during sepsis, closely paralleling disease progression. Both NLRP3-CASP1-GSDMD and BAX-CASP3-GSDME pyroptosis pathways were time-dependently activated in hepatocytes under septic conditions. Notably, hepatocyte-specific FSTL1 knockdown attenuated ROS production, suppressed both pyroptotic pathways, reduced hepatic inflammation and tissue damage, and improved survival in septic mice.DiscussionFSTL1 plays a critical role in promoting hepatocellular pyroptosis during sepsis-induced liver injury through dual activation of NLRP3-CASP1-GSDMD and BAX-CASP3-GSDME pathways. Targeting FSTL1 may represent a promising novel therapeutic strategy for sepsis management.
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BibTeX
@article{duan2026fstl1,
title = {{FSTL1 aggravates LPS-induced liver injury through the NLRP3-CASP1-GSDMD and BAX-CASP3-GSDME pyroptosis pathways}},
author = {Yu Duan and Zechen Shan and Renqi Yao and Yuguo Chen},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1984625},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1984625},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - FSTL1 aggravates LPS-induced liver injury through the NLRP3-CASP1-GSDMD and BAX-CASP3-GSDME pyroptosis pathways
AU - Yu Duan
AU - Zechen Shan
AU - Renqi Yao
AU - Yuguo Chen
PY - 2026
DA - 2026/10/30
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1984625
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1984625
AB - IntroductionHepatocellular pyroptosis and its proinflammatory effects critically contribute to the pathology of acute liver injury. FSTL1, a secreted glycoprotein, has been implicated in regulating multiple cell death pathways and promoting inflammatory disease progression. However, the regulatory mechanisms of FSTL1-mediated hepatocellular pyroptosis in sepsis-induced liver injury remain poorly understood. This study aimed to investigate the role of FSTL1 in hepatocyte pyroptosis during sepsis and evaluate its therapeutic potential.MethodsSeptic liver injury was induced by intraperitoneal LPS injection in mice. Hepatocyte-specific FSTL1 knockdown was achieved via AAV-mediated gene silencing prior to LPS challenge. Serum and liver tissues were collected at designated time points. We measured serum FSTL1, liver function markers (AST, ALT), evaluated histopathological changes, ROS production, pyroptosis pathway activation (NLRP3-CASP1-GSDMD and BAX-CASP3-GSDME), hepatic inflammation, and survival rates.ResultsSerum FSTL1 was significantly elevated and positively correlated with liver injury severity. Hepatic FSTL1 expression progressively increased during sepsis, closely paralleling disease progression. Both NLRP3-CASP1-GSDMD and BAX-CASP3-GSDME pyroptosis pathways were time-dependently activated in hepatocytes under septic conditions. Notably, hepatocyte-specific FSTL1 knockdown attenuated ROS production, suppressed both pyroptotic pathways, reduced hepatic inflammation and tissue damage, and improved survival in septic mice.DiscussionFSTL1 plays a critical role in promoting hepatocellular pyroptosis during sepsis-induced liver injury through dual activation of NLRP3-CASP1-GSDMD and BAX-CASP3-GSDME pathways. Targeting FSTL1 may represent a promising novel therapeutic strategy for sepsis management.
SN - 1664-3224
ER -