Inter-organ crosstalk in systemic inflammation: a narrative review of molecular mechanisms and pharmacological modulation in the muscle-adipose-liver axis

Systemic inflammation is increasingly recognized as a network-driven process sustained by dynamic inter-organ communication rather than isolated tissue responses. The muscle-adipose-liver axis plays a central role in this framework, integrating metabolic and immune signals that regulate systemic homeostasis. During inflammatory conditions, this coordinated communication becomes dysregulated, contributing to insulin resistance, chronic inflammation, and multi-organ dysfunction. Inter-organ crosstalk is mediated by multiple interconnected signaling layers, including cytokines, extracellular vesicles, lipid mediators, and metabolites, which collectively shape local and systemic responses. Emerging evidence highlights the importance of extracellular vesicles as long-distance carriers of molecular information, as well as the role of lipid mediators and metabolic reprogramming in linking inflammation with metabolic pathways. Pharmacological modulation of these networks represents a promising therapeutic strategy. While current interventions targeting cytokines and metabolic pathways show systemic benefits, newer approaches focusing on extracellular vesicle signaling and pro-resolving lipid mediators offer opportunities for more precise and context-dependent treatments. Advances in multi-omics and systems pharmacology are further enabling the identification of key regulatory nodes and biomarkers, supporting the development of precision medicine strategies. Overall, understanding and targeting inter-organ communication networks may provide more integrative and effective approaches for the treatment of systemic inflammatory and metabolic diseases.