ACAT1‐Mediated SP1‐K694 Lactylation Promotes M1 Macrophage Polarization via TREM1 Transcription in COPD
Year: 2026
Type: article
Abstract: Aberrant macrophage polarization is one of the key mechanisms underlying chronic obstructive pulmonary disease (COPD), but the underlying processes have not yet been fully elucidated. Lactylation is a novel lactate-derived post-translational modification and is relatively active in M1 macrophages. This study identified SP1 lactylation at lysine 694 (SP1-K694la), which was elevated in Cigarette Smoke Extract(CSE)-induced macrophages and COPD mice and enhanced SP1 enrichment at the TREM1 promoter. TREM1 knockdown reduced M1 macrophages. The SP1-K694R mutation (mimicking delactylation) decreased SP1-K694la, reduced SP1 enrichment at the TREM1 promoter, and downregulated M1 macrophages under CSE treatment. In contrast, the SP1-K694Q mutation (mimicking constitutive lactylation) increased SP1-K694la, enhanced SP1 enrichment at the TREM1 promoter, and promoted M1 macrophage polarization. Furthermore, TREM1 knockdown alleviated SP1-K694la-mediated increase in M1 macrophages and reduced secretion of IL-1β, IL-6, and TNF-α. In addition, ACAT1 was identified as a lactyltransferase for SP1-K694la. In COPD patients, lactate levels, Pan-Kla, LDHA, SP1-K694la, and TREM1 were elevated. Lactate levels correlated positively with smoking index and were higher in GOLD 3-4 than in GOLD 1 patients, while TREM1 mRNA correlated negatively with FEV1, FEV1%pred, and FEV1/FVC.ACAT1 acts as a lactyltransferase, increasing SP1-K694la to enhance TREM1 transcription, which promotes M1 polarization and airway inflammation in COPD.
Source: Advanced Science
DOI: 10.1002/advs.78021
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,730
Awards: G4648565888, G5355189387
OpenAlex ID: W7214517371