Targeting LUM-mediated inflammatory cell communication and fibroblast apoptosis with SFI in Heart Failure.

Abstract

Heart failure (HF) remains a major contributor to global morbidity and mortality, characterized by complex pathological processes including inflammation and aberrant intercellular communication. Shenfu Injection (SFI), a traditional Chinese herbal preparation, shows beneficial clinical outcomes in HF, but the precise molecular basis governing its effects on the cardiac microenvironment is not fully elucidated. We integrated single-cell RNA sequencing (scRNA-seq), bulk transcriptomics, and machine learning to investigate the cellular landscape, intercellular communication networks, and key apoptosis-related genes in HF. Cell-cell interaction analyses were performed to dissect signaling dynamics. The cardioprotective effects of SFI were validated in a murine HF model. scRNA-seq revealed a pro-inflammatory microenvironment characterized by immune cell activation and elevated apoptosis, particularly in fibroblast populations. Cell-cell communication analysis highlighted a dramatic increase in intercellular signaling activity in HF, with pro-inflammatory pathways like MAPK being central to this pathological crosstalk. Through LASSO regression and pathway analysis, LUM (Lumican) was identified as a fibroblast-specific, apoptosis-related hub gene. SFI treatment significantly downregulated LUM expression and the associated p38/p53 pathway, thereby limiting cardiomyocyte apoptosis, reducing inflammatory cytokine levels (TNF-α, IL-6), improving cardiac performance, and alleviating myocardial injury. This study identifies LUM as a critical regulator at the intersection of apoptosis, inflammation, and cellular communication in HF. We demonstrate that SFI exerts its cardioprotective effects by modulating the LUM-mediated signaling axis, thereby disrupting pathological intercellular signaling and mitigating inflammation. These findings offer novel mechanistic insights, positioning the LUM-centric inflammatory communication network as a potential therapeutic target for HF.