Metabolic Reprogramming-Driven Lactylation: Emerging Mechanisms Linking DNA Damage Repair and Chemoresistance in...

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Lactylation is an emerging post-translational modification derived from lactate.
• Tumors often exhibit enhanced glycolysis and lactate accumulation.
• Lactylation may connect tumor metabolic reprogramming, epigenetics, and DNA damage repair.

Purpose of the Study:

• To explore the role of lactylation in DNA damage repair pathways.
• To investigate the potential of lactylation as a target for cancer therapy.
• To understand the link between lactylation, tumor metabolism, and therapeutic resistance.

Main Methods:

• Review of recent studies on lactylation in cancer models.
• Analysis of specific lactylation events (e.g., XRCC1, H4K12, BLM, NBS1, RAD51, XLF).
• Examination of potential therapeutic targets and strategies.

Main Results:

• Lactylation is associated with multiple DNA repair pathways (BER/SSBR, NER, HR, NHEJ).
• Specific lactylation events correlate with therapy resistance (e.g., H4K12 lactylation and PARP inhibitor resistance).
• Lactylation of key proteins (XRCC1, BLM, NBS1, RAD51, XLF) impacts DNA repair.

Conclusions:

• Lactylation modulates DNA repair and therapeutic response in a context-dependent manner.
• Targeting lactylation regulators (e.g., LDHA, MCT1/4) or using lactylation-inhibiting peptides may improve treatment efficacy.
• Clinical translation is limited by heterogeneity, metabolic plasticity, toxicity, and validation issues.