The release and activity of HMGB1 in ferroptosis

Area of Science:

• Immunology
• Cell Biology
• Biochemistry

Background:

• Damage-associated molecular patterns (DAMPs) signal danger to the innate immune system during cell death.
• The role of DAMPs in ferroptosis, a specific type of regulated necrosis involving iron and lipid peroxidation, is not well understood.
• High-mobility group box 1 (HMGB1) is a known DAMP, but its release during ferroptosis requires further investigation.

Purpose of the Study:

• To investigate the release of HMGB1 during ferroptosis.
• To elucidate the mechanisms controlling HMGB1 release in ferroptosis, particularly the role of autophagy.
• To determine the receptor mediating HMGB1-induced inflammation in response to ferroptotic cells.

Main Methods:

• Utilized various ferroptosis activators (erastin, sorafenib, RSL3, FIN56) in cancer and non-cancer cell lines.
• Employed genetic (ATG5/7 knockout) and pharmacologic (bafilomycin A1, chloroquine) inhibition of autophagy.
• Assessed HMGB1 release, acetylation, and HDAC inhibition.
• Investigated the role of AGER and TLR4 in mediating macrophage inflammatory responses.

Main Results:

• Ferroptosis activators induce the release of HMGB1 from both cancer and non-cancer cells.
• Autophagy is essential for HMGB1 release during ferroptosis; its inhibition blocks release.
• Autophagy-mediated histone deacetylase (HDAC) inhibition promotes HMGB1 acetylation and subsequent release.
• AGER, not TLR4, is required for HMGB1-induced inflammation in macrophages responding to ferroptotic cells.

Conclusions:

• HMGB1 is a DAMP released in an autophagy-dependent manner during ferroptosis.
• The mechanism involves autophagy-mediated HDAC inhibition leading to HMGB1 acetylation and release.
• AGER mediates HMGB1-driven inflammation, suggesting HMGB1 inhibition as a potential therapeutic strategy for ferroptosis-associated diseases.