Purpose <p>Myocardial fibrosis is a key pathological feature of heart failure (HF) linked to aberrant macrophage polarization. Although the traditional Chinese medicine Shenfu injection (SFI) clinically improves HF and has been found to inhibit M1 macrophage polarization and fibrosis, its mechanisms remain unclear. This study aimed to elucidate how SFI regulates macrophage-cardiac fibroblasts (CFs) communication — specifically via exosomal miR-155-5p from M1 macrophages.</p> Methods <p>An isoproterenol (ISO)-induced mouse model of HF was established to assess the effects of SFI on cardiac function, inflammatory cytokines, myocardial fibrosis, and the expression and localisation of miR-155-5p. <i>In vitro</i>, an M1 macrophage model was generated using lipopolysaccharide (LPS)-stimulated RAW264.7 cells, which were then treated with SFI or an miR-155-5p inhibitor. Exosomes from these cells were isolated and co-cultured with CFs to evaluate the miR-155-5p/SOCS1 pathway and fibrosis markers.</p> Results <p>miR-155-5p expression was markedly upregulated and localized to infiltrating cardiac macrophages in mice. SFI treatment reduced levels of TNF-α, IL-6, and miR-155-5p, along with improved fibrosis and cardiac function. <i>In vitro</i>, SFI significantly decreased miR-155-5p levels in exosomes derived from M1 macrophages. Co-culture with exosomes from macrophages that were either SFI-treated or miR-155-5p-inhibited suppressed CFs activation. This was demonstrated by reduced expression of fibrosis markers (α-SMA, Col I, Col III), as well as decreased miR-155-5p levels and restored SOCS1 expression.</p> Conclusion <p>This study demonstrates that SFI alleviates myocardial fibrosis by suppressing macrophage-derived exosomal miR-155-5p and restoring SOCS1 in CFs, thereby providing a mechanistic basis for its established clinical efficacy in HF. Our findings highlight the potential of targeting the macrophage-fibroblast miR-155-5p/SOCS1 axis as a therapeutic strategy.</p> Graphical Abstract <p></p>