MAMDC2 drives microglia-mediated neuroinflammation via CAND1-dependent IκBα ubiquitination and is targetable by...

Sustained microglial activation is a common feature of many neurological disorders, yet the upstream molecular amplifiers that sustain this process remain poorly defined. Our earlier work identified MAM domain-containing 2 (MAMDC2) as an immune regulator enriched in microglia with an established role in antiviral immunity. However, whether and how MAMDC2 shapes microglial inflammatory activation and neuroinflammation has remained largely unexplored. Here, we show that MAMDC2 is strongly induced in microglia after challenge with LPS or HSV-1, both in vitro and in vivo, where it amplifies the microglial inflammatory response. Mechanistically, MAMDC2 associates with Cullin-associated and neddylation-dissociated protein 1 (CAND1) and facilitates K48-linked ubiquitination and proteasomal degradation of IκBα, thereby enhancing NF-κB-dependent inflammatory signaling and activating the downstream JAK2-STAT1 pathway. In male mice, loss of MAMDC2 alleviated neuroinflammatory pathology and glial activation, and improved motor behavior. By combining virtual screening with experimental validation, we further identified Artemvulactone E (AE), a sesquiterpenoid from Artemisia vulgaris L., as a small molecule that targets MAMDC2. AE disrupts the MAMDC2-CAND1 interaction, thereby dampening NF-κB-dependent microglial inflammation and protecting against LPS-induced pathology in vivo. Together, these findings establish MAMDC2 as a previously unrecognized upstream amplifier of microglial inflammation acting through the CAND1-IκBα-NF-κB axis and identify AE as a promising pharmacological modulator of MAMDC2 for the treatment of neuroinflammatory disorders.