Microproteins in Metabolism

Metabolism is a complex network of biochemical pathways that break down macromolecules to produce energy essential for cellular function. Disruptions in metabolic homeostasis are closely linked to noncommunicable diseases (NCDs) such as cardiovascular disease, type 2 diabetes, and cancer, which are leading causes of death worldwide. Many NCD-associated conditions, including obesity and insulin resistance, stem from metabolic dysfunction, and current therapies often fall short in preventing disease progression, highlighting the need for novel therapeutic targets. Microproteins, small proteins of ≤100-150 amino acids, have recently emerged as important regulators of metabolism. Encoded by short open reading frames (sORFs), many of these proteins were historically overlooked due to their small size and misclassification as noncoding RNAs. Advances in genomics and proteomics have revealed that these sORFs can encode functional proteins with critical roles in metabolic pathways. In this review, we highlight the microproteins involved in energy metabolism, mitochondrial function, and nutrient signaling. We discuss their emerging roles in the pathogenesis of NCDs and explore their potential as novel therapeutic targets. As microprotein biology continues to evolve, these small but powerful regulators may offer new strategies for treating metabolic dysfunction and reducing the global burden of NCDs.