Hypoxia Aggravates Myocardial Ischemia/Reperfusion Injury Through the Promotion of Ferroptosis via ACSL4 Lactylation

Area of Science:

• Biochemistry
• Molecular Biology
• Cardiovascular Research

Background:

• Myocardial ischemia/reperfusion injury (MIRI) exacerbates cardiac damage.
• Ferroptosis, an iron-dependent cell death, is a key mediator in MIRI.
• The role of lactylation, a novel epigenetic modification, in MIRI-associated ferroptosis is not well understood.

Purpose of the Study:

• To investigate the mechanistic link between lactylation and ferroptosis in MIRI.
• To identify key proteins involved in lactylation-mediated ferroptosis during MIRI.

Main Methods:

• Utilized hypoxia/reoxygenation (H/R) models with lactate (LA) treatment.
• Assessed protein expression, lactylation status, and stability of ACSL4.
• Performed site-specific analysis to identify lactylation sites on ACSL4.
• Employed LDHA knockdown and ACSL4 overexpression for functional studies.
• Validated findings in vivo using MIRI models.

Main Results:

• Hypoxia/reoxygenation and lactate treatment increased ACSL4 protein expression, lactylation, and stability.
• Lysine 83 (K83) was identified as the critical lactylation site on ACSL4.
• LDHA knockdown reduced lactate levels, attenuated ferroptosis, and protected against MIRI, an effect reversed by ACSL4 overexpression.
• In vivo studies confirmed LDHA depletion ameliorated MIRI-induced cardiac dysfunction and ferroptosis.

Conclusions:

• Lactylation of ACSL4 promotes ferroptosis, exacerbating MIRI.
• The lactylation-ACSL4 axis is a crucial mechanism in MIRI pathogenesis.
• Targeting the lactylation-ACSL4 pathway presents a potential therapeutic strategy for MIRI.