Lactylation-associated CXCL12-mediated intercellular communication in rheumatic heart disease valves
- 1Department of Cardiac Surgery, Zhongshan Hospital Fudan University, 180 Fenglin Road, Shanghai, 200032, China
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.
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BibTeX
@article{zhai2026lactylationassociated,
title = {{Lactylation-associated CXCL12-mediated intercellular communication in rheumatic heart disease valves}},
author = {Junyu Zhai and Zheng Zuo and Tao Yan and Fangyu Liu and Jiaxing Liu and Kai Zhu and Hao Lai and Chunsheng Wang and Jun Li},
journal = {Journal of Translational Autoimmunity},
year = {2026},
month = oct,
doi = {10.1016/j.jtauto.2026.100405},
url = {https://doi.org/10.1016/j.jtauto.2026.100405},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Lactylation-associated CXCL12-mediated intercellular communication in rheumatic heart disease valves
AU - Junyu Zhai
AU - Zheng Zuo
AU - Tao Yan
AU - Fangyu Liu
AU - Jiaxing Liu
AU - Kai Zhu
AU - Hao Lai
AU - Chunsheng Wang
AU - Jun Li
PY - 2026
DA - 2026/10/13
JO - Journal of Translational Autoimmunity
DO - 10.1016/j.jtauto.2026.100405
UR - https://doi.org/10.1016/j.jtauto.2026.100405
AB - 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.
SN - 2589-9090
ER -