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Lipids are the major energy reservoir, but excessive fat accumulation drives immune cell trapping, chronic inflammation, autoimmunity, and cancer. Lipid synthesis, secretion, degradation, and the shuttling to cellular organelles and compartments are still poorly investigated in all cell types of the mammalian body. The major routes of FA uptake are dietary uptake, lipolysis, and de novo synthesis. We highlight disease associations zooming in on the Signal Transducer and Activator of Transcription 1/3/5 (STAT1/3/5) molecules in association with cytokine, growth factors, and hormone action, steering lipid metabolism. We compare STAT-lipid crosstalk from nuclear and mitochondrial perspectives, highlighting roles in immunity, metabolic diseases, and cancer, and providing insights into key regulatory mechanisms of lipid metabolism. A high degree of cellular flexibility in metabolic adaptation explains the need for fine-tuning, in which STAT molecules can function as rheostats to maintain energy equilibrium within cellular compartments. This concept bridges, e.g., high-energy flux or the Warburg effect, with the Hydride Transfer Complex upon low-energy provision. Another interesting STAT1/3/5 aspect is their Lipid droplet (LD) association and LD formation. LDs play key roles in disease initiation or progression, including autoimmunity or cancer, as well as chronic inflammatory diseases due to their role in (1) lipotoxicity, (2) cell death regulation, (3) immune system amelioration, and (4) energy provision. Finally, the therapeutic consequences of the angles are outlined, along with future research directions.