Work

Lactylation-associated CXCL12-mediated intercellular communication in rheumatic heart disease valves

Year: 2026

Type: article

Abstract: Background: Rheumatic heart disease (RHD) is characterized by persistent valvular inflammation and fibrosis. Lactate-driven lysine lactylation may couple metabolic stress to inflammatory transcription, but its relationship with CXCL12-mediated immune recruitment in RHD valves remains unclear. Methods: Paired aortic and mitral valve single-cell RNA-sequencing data from three patients with RHD were analyzed, yielding 47,237 quality-controlled cells. CXCL12-producing cell populations were identified, and lactylation-related transcriptional states and inflammatory pathways were assessed in CXCL12-high structural cells using complementary scoring and pseudobulk approaches. CellChat was used to infer CXCL12-mediated intercellular communication, with GSE153555 used for external validation. Human valve interstitial cells (VICs) were treated with lactate, the p300 inhibitor A-485, or the NF-κB inhibitor BAY 11-7082. CXCL12/CXCR4-dependent monocyte chemotaxis was evaluated using THP-1 cells, AMD3100, and a CXCL12-neutralizing antibody. Results: VICs and myofibroblasts were the principal CXCL12-producing cells. Within CXCL12-high structural cells, a higher lactylation-related transcriptional state was associated with enhanced NF-κB and TNF signaling and increased IL6, BIRC3, REL, and TNFAIP3 expression. CellChat supported CXCL12-CXCR4 communication from structural cells to myeloid and lymphoid cells, while external validation confirmed increased CXCL12, IL6, and TNFAIP3 expression in diseased valves. In VICs, lactate increased Pan-Kla, H3K9la, H3K14la, and CXCL12 expression and secretion. A-485 attenuated lactylation-associated CXCL12 induction, whereas BAY 11-7082 suppressed NF-κB activation and CXCL12 expression. Lactate-conditioned medium enhanced THP-1 migration and inflammatory gene expression, which were reduced by pathway inhibition or CXCL12/CXCR4 blockade. Conclusion: These findings link lactylation-associated metabolic signaling in RHD valve structural cells to NF-κB-dependent CXCL12 production and CXCL12-CXCR4-mediated monocyte recruitment, providing a mechanistic framework for stromal-immune communication in RHD.

Source: Journal of Translational Autoimmunity

DOI: 10.1016/j.jtauto.2026.100405