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Published on: February 10, 2015
Targeting ACOT1-SLC25A5 Axis attenuates LPS-induced acute liver injury by inhibiting ferroptosis and inflammatory
Chengzhu Xu1, Shun Wang1, Xiyang Wang1
1Children's Medical Center of Anhui Medical University, The Fifth School of Clinical Medicine of Anhui Medical University, Hefei 230051, China; Department of Pediatric Critical Care Medicine, Anhui Provincial Children's Hospital, Hefei, 230051, China.
Abstract:
Sepsis associated acute liver injury is a major contributor to multiple organ dysfunction and mortality in critically ill patients. ACOT1 has emerged as a promising therapeutic target, demonstrated to inhibit disseminated intravascular coagulation through its anti-ferroptosis activity. However, its specific function and mechanistic role in the context of during endotoxemia-induced liver injury have not been elucidated. This study demonstrates that ferroptosis was markedly activated in both lipopolysaccharide (LPS)-stimulated AML12 hepatocytes and LPS-induced acute liver injury mouse models. RNA sequencing and bioinformatics analyses identified ACOT1 as the most significantly downregulated genes following LPS stimulation. Functionally, ACOT1 overexpression upregulated GPX4 and SLC7A11 expression, reduced mitochondrial ROS and Fe2+ accumulation, which ultimately attenuated LPS-induced hepatocyte ferroptosis. Mechanistically, ACOT1 overexpression activated PPARγ, thus suppressing NF-κB pathway activation and inflammatory responses thereafter. IP-MS and immunofluorescence staining confirmed that SLC25A5 interacts with ACOT1 and functions as a molecular partner in regulating hepatocyte ferroptosis by reducing mitochondrial ROS and Fe2+ levels. Protein interaction analysis between ACOT1 and SLC25A5 showed a Rosetta score of -271.16 kcal/mol, indicating strong binding affinity. Collectively, our results identified ACOT1 as a novel inhibitor of ferroptosis in LPS-induced acute liver injury. ACOT1 exerts protective effects by modulating the PPARγ/NF-κB signaling axis and cooperating with SLC25A5 to regulate oxidative stress-driven ferroptosis. These results highlight ACOT1 as a potential regulator for inflammatory liver injury.
Insights
Acyl-CoA thioesterase 1 (ACOT1) inhibits ferroptosis in acute liver injury caused by lipopolysaccharide (LPS). ACOT1 protects liver cells by regulating oxidative stress and inflammation via the PPARγ/NF-κB pathway and interacting with SLC25A5.
Area of Science:
- Hepatology
- Molecular Biology
- Immunology
Background:
- Sepsis-associated acute liver injury (ALI) is a critical factor in patient mortality.
- Acyl-CoA thioesterase 1 (ACOT1) shows potential in treating disseminated intravascular coagulation via anti-ferroptosis activity.
- The role of ACOT1 in endotoxemia-induced ALI remains unclear.
Purpose of the Study:
- To investigate the function and mechanism of ACOT1 in lipopolysaccharide (LPS)-induced acute liver injury.
- To determine ACOT1's role in regulating ferroptosis and inflammation in hepatocytes.
Main Methods:
- Utilized lipopolysaccharide (LPS)-stimulated AML12 hepatocytes and mouse models of LPS-induced ALI.
- Performed RNA sequencing, bioinformatics analysis, and molecular assays (IP-MS, immunofluorescence).
- Investigated the effects of ACOT1 overexpression on ferroptosis markers, oxidative stress, and signaling pathways (PPARγ, NF-κB).
Main Results:
- Ferroptosis was activated in LPS-stimulated hepatocytes and ALI mouse models.
- ACOT1 was significantly downregulated following LPS stimulation.
- ACOT1 overexpression reduced ferroptosis by upregulating GPX4 and SLC7A11, decreasing mitochondrial reactive oxygen species (ROS) and Fe2+ accumulation.
- ACOT1 activated PPARγ, suppressed NF-κB signaling, and reduced inflammation.
- SLC25A5 was identified as a binding partner of ACOT1, cooperating to reduce mitochondrial ROS and Fe2+ levels.
Conclusions:
- ACOT1 acts as a novel inhibitor of ferroptosis in LPS-induced ALI.
- ACOT1 protects against liver injury by modulating the PPARγ/NF-κB axis and cooperating with SLC25A5.
- ACOT1 is a potential therapeutic target for inflammatory liver injury.
