NOD2-mediated HDAC6/NF-κb signalling pathway regulates ferroptosis induced by extracellular histone H3 in acute liver...

Area of Science:

• Hepatology
• Immunology
• Cellular Biology

Background:

• Acute liver failure (ALF) presents a critical health challenge with high mortality rates.
• Understanding the mechanisms driving ALF is crucial for developing effective treatments.
• Hepatic macrophages play a significant role in liver injury and inflammation.

Purpose of the Study:

• To investigate the role of extracellular histone H3 in inducing ferroptosis in hepatic macrophages during ALF.
• To elucidate the underlying molecular mechanisms, focusing on the NOD2, HDAC6, and NF-κb pathways.
• To explore potential therapeutic interventions targeting this pathway.

Main Methods:

• Utilized RAW264.7 macrophages and C57BL/6 mice models.
• Administered lipopolysaccharide (LPS), D-galactosamine (D-Gal), histone H3, histone H3 antibody, Muramyl Dipeptide (MDP), and HDAC6-siRNA.
• Detected key molecules involved in ferroptosis, NOD2 signaling, HDAC6 activity, and the NF-κb pathway.

Main Results:

• Extracellular histone H3 induced ferroptosis in macrophages, characterized by increased Fe²⁺ and ROS, and decreased GPX4 and GSH levels.
• MDP exacerbated histone H3-induced ferroptosis, upregulating NOD2, HDAC6, p-P65, and IκBα.
• HDAC6-siRNA ameliorated ferroptosis by downregulating HDAC6, p-P65, and IκBα, but did not affect NOD2 levels.
• In vivo studies confirmed increased NOD2, HDAC6, NF-κb pathway activation, and ferroptosis in ALF mice, which were modulated by histone H3 and its antibody.

Conclusions:

• Extracellular histone H3 induces ferroptosis in hepatic macrophages in ALF.
• This process is mediated by the NOD2-mediated regulation of the HDAC6/NF-κb signaling pathway.
• Targeting this pathway presents a promising therapeutic strategy for acute liver failure.