UCP3 (uncoupling protein 3) is a mitochondrial transmembrane transporter predominantly expressed in skeletal muscle that plays a multifaceted role in energy metabolism 1. Originally characterized as a proton leak channel that uncouples oxidative phosphorylation from ATP synthesis 2, UCP3's primary function remains controversial. Emerging evidence suggests uncoupling may be a secondary consequence rather than the primary function, with UCP3 potentially serving as a metabolite transporter, particularly for fatty acids or lipid peroxides 34. UCP3 critically regulates substrate utilization by favoring lipid oxidation during high-fat conditions and fasting, while also promoting glucose uptake and oxidation 1. The protein exhibits inducible proton transport activity activated by fatty acids, thyroid hormones, and catecholamines 1. Additional proposed functions include attenuating reactive oxygen species (ROS) production and protecting against oxidative damage 4. UCP3 is upregulated during fasting to enhance lipid utilization while simultaneously suppressing uncoupling activity, optimizing whole-body energy homeostasis 1. Clinically, UCP3 variants have been associated with obesity and severe early-onset obesity, particularly when co-occurring with variants in other metabolic genes like PCSK1 56. UCP3 remains a promising therapeutic target for metabolic disorders, though its precise mechanistic role requires further investigation.