Macrophage-Driven Immuno-Fibrosis in Heart Failure: Targeting Macrophage-Fibroblast Crosstalk for Drug Discovery

Heart failure affects more than 64 million people worldwide and remains a leading driver of cardiovascular morbidity and mortality. Adverse cardiac remodeling, sustained inflammation, followed by progressive interstitial fibrosis, is a unifying feature of both heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Cardiac macrophages occupy a central position in this process. They orchestrate the inflammatory response after ischemic and non-ischemic injury, initiate fibroblast activation through cytokines, chemokines, and bioactive lipids, and shape the resolution programs that determine whether the myocardium heals or scars. Single-cell transcriptomic and lineage-tracing studies have now mapped a heterogeneous spectrum of resident and monocyte-derived macrophages engaged in bidirectional crosstalk with cardiac fibroblasts. Despite this mechanistic progress, no approved heart failure therapy specifically targets this immune-fibrotic axis.Current heart failure pharmacotherapies, including neurohormonal blockade, SGLT2 inhibitors, and recently introduced anti-inflammatory agents, improve outcomes but do not directly disrupt the macrophage-fibroblast circuit that drives myocardial fibrosis. This Research Topic seeks to consolidate emerging insights into macrophage-mediated inflammation and macrophage-fibroblast crosstalk in heart failure and translate them into coherent pharmacological strategies. We will assemble mechanistic studies that identify tractable molecular nodes, translational work that bridges preclinical models with human disease, and pharmacology-focused contributions evaluating small molecules, biologics, RNA therapeutics, and repurposed agents at the immune-fibrotic interface. The collection will also examine biomarker development, patient stratification, and the use of advanced models, including human iPSC-derived systems and regenerative species such as Acomys, to accelerate target identification and validation. The intended outcome is a focused, peer-reviewed resource that informs the next generation of drug development against immuno-fibrosis in heart failure.We welcome Original Research, Reviews, Mini-Reviews, Systematic Reviews, Perspectives, addressing but not limited to, the following themes:• Macrophage polarization, plasticity, and function in heart failure as drug targets• Bidirectional macrophage-fibroblast signaling through cytokines, chemokines, bioactive lipids, extracellular vesicles, and direct cell-cell contact• Pharmacological targeting of macrophage recruitment, efferocytosis, and resolution programs• Fibroblast-to-myofibroblast transitions and strategies for their reversal• Drug discovery and repurposing for cardiac fibrosis: small molecules, biologics, antisense oligonucleotides, siRNA, CAR-T• HFpEF-specific inflammatory and metabolic mechanisms for new drug development• Translational biomarkers and imaging of cardiac immuno-fibrosis• Insights from regenerative models (Acomys, zebrafish, neonatal mammals)• Translational lessons from clinical trials of immunomodulators in heart failure Topic editors: Ahmed Abdel-Latif, Edward Thorp, Parisa Shabani, Lukas Tomas Source: https://www.frontiersin.org/research-topics/82520/macrophage-driven-immuno-fibrosis-in-heart-failure-targeting-macrophage-fibroblast-crosstalk-for-drug-discovery