ACAT1-mediated lactylation reprogramming governs immune-stromal crosstalk in ulcerative colitis

Area of Science:

• Biochemistry
• Immunology
• Gastroenterology

Background:

• Ulcerative colitis (UC) is a chronic inflammatory bowel disease with increasing incidence and colorectal cancer risk.
• The role of lactylation, a novel post-translational modification, in UC pathogenesis is not well understood.

Purpose of the Study:

• To elucidate the mechanistic involvement of lactylation in UC pathogenesis.
• To identify key lactylation-associated genes and their role in the UC immune microenvironment.
• To explore ACAT1 as a potential diagnostic biomarker and therapeutic target for UC.

Main Methods:

• Integrative analysis of GEO datasets, differential expression profiling, WGCNA, and PPI network reconstruction.
• Machine learning algorithms identified ACAT1 as a hub gene.
• Immune microenvironment profiling (CIBERSORT, ssGSEA, scRNA-seq) and Mendelian randomization analysis were performed.

Main Results:

• ACAT1 was identified as a central lactylation-associated hub gene in UC.
• Significant myeloid cell heterogeneity was observed in UC, with causal immune-UC relationships confirmed.
• ACAT1 downregulation correlated with specific immune cell profiles in active UC.
• ACAT1 overexpression reduced lactate accumulation and lactylation in vitro and in vivo models.

Conclusions:

• ACAT1 is a master regulator of lactate metabolism and protein lactylation in UC pathogenesis.
• A lactylation subtype stratification system and immune-stromal interaction network were developed.
• ACAT1 shows potential as a diagnostic biomarker and therapeutic target for precision UC management.