Lactylation-Related Gene Signature and Immune Infiltration Crosstalk in Heart Failure: Insights From Bulk and Single-Cell Transcriptomics

Heart failure (HF), with varied symptoms caused by cardiac strain or damage, has high morbidity and mortality. Protein lactylation, a post-translational modification, regulates immune and cardiovascular processes, but its role in HF's immune microenvironment remains underexplored. Differentially expressed lactylation-related genes (LacRGs) were identified by intersecting HF differentially expressed genes with LacRG data sets. Unsupervised clustering categorized patients with HF into LacRG-based subgroups. An LacRG diagnostic model was developed to assess associations with immune cell infiltration, immunotherapy potential, and single-cell RNA sequencing expression patterns. HF mouse models were constructed and verified for LacRG expression. In 200 HF versus 166 non-HF samples, 38 differentially expressed LacRGs were identified, revealing distinct immune landscapes. Two LacRG clusters exhibited unique functional enrichment and immunologic features. A 14-gene LacRG signature distinguished HF from controls with high accuracy (area under the curve: 0.999, 1.000, 0.744). Single-cell RNA sequencing (GSE145154) revealed reduced lactylation scores in fibroblast, macrophage, T-cell, and NK-cell subsets in HF, alongside characterization of altered cellular subtypes and activated signaling pathways within these populations. External data sets (GSE46224, GSE116250) identified 6 hub genes-HBB, EXT1, CENPA, NT5E, STAT4, and CAPN5, which were validated in HF mouse models. In addition, analysis of HF dataset further indicated higher LacRG scores in heart failure with preserved ejection fraction than in reduced ejection fraction. Lactylation modification is closely linked to HF's immune microenvironment. A 14-gene LacRG signature and 6 hub genes provide novel insights into HF pathophysiology and potential therapeutic avenues. Further studies are warranted to validate their regulatory roles in HF through immune microenvironmental mechanisms.