Synergy and antagonism of inflammatory signaling pathways in cardiovascular disease: from molecular crosstalk to stem cell-based and pharmacological therapeutic strategies

Cardiovascular diseases are driven by dysregulated inflammatory signaling networks in which pathways overlap and interact through synergistic, antagonistic, and feedback mechanisms, yet conventional single-pathway-targeted therapies have shown limited efficacy due to compensatory activation and context-dependent signaling plasticity. This review evaluates major inflammatory pathways relevant to CVDs, with a focus on three principal functional modules: the NF-κB–NLRP3–cGAS-STING axis, which amplifies sterile inflammation through sequential priming, inflammasome activation, and cytosolic DNA sensing; the JAK–STAT–NF-κB axis, which sustains chronic inflammation through cytokine-driven feedback loops and contributes to senescence-associated secretory phenotype and fibrotic remodeling; and the Wnt/β-catenin–TGF-β axis, which balances tissue repair and fibrosis in a context- and time-dependent manner. Additional pathways, including PI3K/Akt, MAPK, and Notch, are discussed in the context of their modulatory roles within this framework, and their interactions are described across the acute, subacute, and chronic stages of cardiovascular inflammation. We further analyze how mesenchymal stem cells and their extracellular vesicles modulate multiple nodes of this network, and evaluate pharmacological strategies including dual-target small molecules, STING inhibitors, epigenetic therapies, and combined stem cell–drug regimens. We propose that therapeutic approaches that disrupt pathological crosstalk interactions, as opposed to targeting individual inflammatory pathways in isolation, may offer a more rational strategy. The convergence of stem cell biology, EV engineering, multi-faceted pharmacology, single-cell multi-omics, spatial transcriptomics, and AI-based modeling may enable the identification and exploitation of time-window crosstalk nodes for therapeutic purposes, though cellular heterogeneity, therapeutic safety windows, and compensatory events remain significant barriers to translation. A network-based approach in combination with stem cell therapy and pharmacology, guided by advanced spatiotemporal and multi-omics technologies, may represent the best opportunity for precision management of inflammatory CVDs.