Table 3 Pioneer histone lactylation “reader” proteins and their mechanistic functions.

From: Lactylation as a metabolic-epigenetic switch in cancer: dual roles in cell death resistance and therapeutic vulnerability

Reader protein

Target modification

Critical binding motif

Structural mechanism

Biological outcome

Ref

BRG1

H3K18la

Bromine domain

N/A

Promotes mesenchymal–epithelial transition (MET) during cellular reprogramming by activating core pluripotency genes (e.g., OCT4, NANOG, SOX2).

[19]

DPF2

H3K14la

Dual PHD zinc-finger domains (PHD1-PHD2)

The lactyl group of H3K14la is anchored within a hydrophobic pocket in PHD1. The N-terminal α-helix of H3 engages PHD2 via electrostatic and hydrogen-bonding interactions (e.g., D346, L342).

Drives tumorigenesis by activating oncogene expression (e.g., SEMA5A, ROCK1), facilitating cell cycle progression, and anti-apoptotic signaling.

[20]

TRIM33

H3K18la

PHD-bromodomain

Specific recognition is mediated by dual hydrogen bonds between the lactyl carbonyl group and residue E981 in the PHD-bromodomain, conferring selectivity over acetylated lysine.

Critically regulates macrophage polarization from pro-inflammatory M1 to reparative M2 states by modulating inflammatory gene transcription.

[21]

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