STAT Signaling in Metabolic Disorders: From Molecular Mechanisms to Therapeutic Implications.

Metabolic disorders such as obesity, type 2 diabetes, metabolic-associated steatotic liver disease, and cardiovascular complications arise from disrupted energy balance, chronic inflammation, and endocrine dysregulation. The signal transducer and activator of transcription (STAT) family functions as a central integrator of hormonal, cytokine, and metabolic cues, playing diverse tissue-specific and context-dependent roles. STAT3 regulates leptin and interleukin 6 signaling to control hypothalamic appetite circuits and maintain hepatic and adipose metabolic homeostasis. STAT5 promotes the activity of growth hormone and insulin-like growth factor 1, while aiding in the maintenance of insulin sensitivity. STAT6 promotes alternative macrophage activation and adipose thermogenesis, whereas STAT1 activates pro-inflammatory and apoptotic pathways that exacerbate metabolic dysfunction. Dysregulated STAT signaling couples immune tone to metabolic stress, driving insulin resistance, steatosis, and organ injury. Therapeutic approaches that modulate STAT pathways, including Janus kinase inhibitors, selective STAT3 and STAT5 modulators, and bioactive natural compounds, have shown metabolic and anti-inflammatory benefits in experimental models. However, the pleiotropic and time-dependent nature of STAT signaling highlights the need for cell-specific and stage-adapted interventions. This review synthesizes current evidence on the roles of STAT proteins in immunometabolic regulation, evaluates advances in STAT-targeted therapies, and outlines future strategies for precise modulation of STAT signaling across metabolic tissues. Integrating single-cell and spatial multi-omics with targeted delivery systems may pave the way for next-generation immunometabolic therapies centered on STAT signaling.