Manganese: biology, physiology and role in disease

Manganese (Mn) has lingered in the shadows as a mere enzymatic cofactor, with its profound role in regulating the most fundamental life processes largely overlooked. This review heralds a "manganese renaissance" - a paradigm shift that elevates Mn from a passive trace element to a dynamic architect of metabolic homeostasis and a critical driver of disease. We synthesize breakthroughs that redefine its biological significance. In addition to enabling reactions for enzymes such as MnSOD, Mn actively governs lipid trafficking via the modulation of the COPII complex, facilitates cGAS/STING signaling for host immune responses, and precisely activates ion transporters and sensors to maintain cellular homeostasis. Dysregulated Mn homeostasis - whether stemming from genetic defects in key transporters (SLC30A10, SLC39A8, SLC39A11, and SLC39A14) or environmentally induced overload - fuels a spectrum of pathologies, including metabolic syndrome, Parkinsonism-like neurodegeneration, hepatic dysfunction, cardiovascular disease, and immune dysfunction. This disruption underscores the irreplaceable role of Mn as a biological linchpin, as its balance is not merely supportive but also central to sustaining health. In the future, we outline translational frontiers - from dietary Mn modulation and transporter-specific therapies for genetic Mn disorders to the elucidation of Mn signaling and the development of exposure guidelines to safeguard public health. This synthesis reaffirms that Mn is far more important than simply functioning as a nutrient. Research into Mn functions has been conducted across biology, environmental science, and medicine, and Mn acts as a master regulator whose emerging mechanisms will reshape our understanding of metabolic health and disease pathogenesis.