Table 1 Evolution of lactylation mechanisms from 2019 to 2025.
Year | Mechanism Development | Notes |
|---|---|---|
2019 | Zhang D et al. first reported p300 as a potential writer of histone lactylation (4). | First reported KAT as the potential writer of histone lactylation. |
2020 | Gaffney DO et al. first reported LGSH-mediated non-enzymatic transfer of lactyl groups to protein Lys residues (generating “LactylLys”) (89). | Mechanistic breakthrough in non-enzymatic lysine lactylation. |
2021 | Moreno-Yruela C et al. reported HDAC1-3 and SIRT1-3 as lactyl-erasers. (HDAC3 exhibits higher efficiency in removing D/L-lactyllysine in vitro.) (13) | Erasers (HDAC1-3/SIRT1-3). |
2023 | Sun L et al. first reported that knockdown of AARS1/2 inhibits the lactylation modification of METTL16K229 (49). | AARS1/2 is first reported as lactyltransferasers. |
2024 | Three independent studies revealed the moonlighting role and specific molecular mechanism of AARS1/2 as lactyltransferases (7,8,9). | First enzymatic mechanism elucidation of AARS1/2 as lactyltransferases. |
Zhang D et al. reported that KCE is directly induced by MGO (16). | Mechanistic breakthrough in non-enzymatic lysine lactylation. | |
Hu X et al. reported that Brg1 acts as a reader for H3K18la (19). Zhai G et al. reported that DPF2 acts as a reader for H3K14la (20). Nunez R et al reported that TRIM33, a bromodomain - containing protein, acts as a novel reader of histone lysine lactylation (21). | Breakthrough in Readers (Brg1/DPF2/TRIM33). | |
Sun S et al. reported that HDAC6 of the HDAC family exhibits dual enzymatic activity in vitro, but functions primarily as a lactyltransferase in cells (15). | in vitro studies suggest delactylase activity under low-lactate conditions, but cellular evidence supports a dominant lactyltransferase role in high lactate cells. | |
2025 | Two independent studies identified two genuine lactyl - CoA synthetases (ACSS2/GTPSCS) and their cooperative mechanism with KATs (KAT2A/p300) in lactylation (10, 11). | Identification of lactyl-CoA synthetases (ACSS2/GTPSCS). |
Zhao Q et al. reported that during the inflammatory response, the KD-la generated non - enzymatically by LGSH can be greatly amplified by nearby cysteine residues. Initially, cysteine residues react with SLG to form a reversible S - lactylthiol intermediate, and then the lactyl molecule undergoes SN transfer to the proximal lysine (17). | Mechanistic breakthrough in non-enzymatic lysine lactylation. |
