Macrophage histone lactylation in atherosclerosis progression: mechanisms, predictive models, and therapeutic potential of Ruan Jian Qing Mai formula.

Aims: This study investigates the role of macrophage histone lactylation-a protein modification-in atherosclerosis progression, particularly in peripheral artery disease (PAD), and evaluates the therapeutic potential of the herbal formula Ruan Jian Qing Mai (RJQM).

Materials And Methods: Weighted gene co-expression network analysis (WGCNA), functional enrichment, and machine learning were used to explore regulatory mechanisms and develop a predictive model for subclinical atherosclerosis. Experimental validation included ApoE-/- mice treated with RJQM and molecular docking to assess drug-protein interactions.

Key Findings: Our analysis identified 2853 histone lactylation-related genes, of which 117 were significantly correlated with macrophage infiltration across carotid, femoral, and infrapopliteal arteries. WGCNA revealed a strong correlation (r = 0.93, P = 7e-47) between the turquoise module and macrophage infiltration, indicating the potential regulatory role of histone lactylation in inflammatory processes. Functional enrichment analysis highlighted the involvement of these proteins in immune responses, particularly cytokine signaling, with hub proteins such as PTPN6 and CASP1 being pivotal. Furthermore, we developed a consensus signature using machine learning methodologies that demonstrated robust predictive power (average area under the curve, AUC > 0.817) for subclinical atherosclerosis. Experimental validation in ApoE-/- mice indicated that the RJQM effectively reduced plaque area by 39 % (P < 0.05) and modulated macrophage pyroptosis and inflammation.

Significance: This research uncovers novel insights into the regulatory mechanisms of macrophage histone lactylation in atherosclerosis and validates the potential of RJQM as a therapeutic strategy, warranting further exploration of its protein modifications and underlying molecular pathways.