Genetics

This article examines emerging evidence that positions NLRC5 as a central regulator of microglial dysfunction in multiple sclerosis through its integration of epigenetic, transcriptomic, and proteomic mechanisms. By leveraging multi-omics datasets and causal inference approaches such as Mendelian randomization, the study demonstrates that NLRC5 links DNA methylation dynamics to downstream inflammatory cell death pathways collectively termed PANoptosis. Functional validation in microglial models further supports its role in PANoptosome activation and neuroinflammatory signaling. These findings provide a mechanistic framework for understanding how coordinated cell death pathways contribute to disease progression and identify NLRC5 as a promising target for therapeutic intervention in neuroinflammatory disorders.