Magnesium Enhances Immune Clearance of P. gingivalis in Macrophages by Suppressing MCU ‐Mediated Mitochondrial Calcium Overload

ABSTRACT P. gingivalis , a keystone periodontal pathogen in periodontitis, is recognized for its capacity to evade host immune clearance. Its intracellular survival leads to both local and systemic infection, thereby increasing the risk of periodontitis and its associated systemic diseases. However, macrophages have limited capacity to clear P. gingivalis , which contributes to disease establishment and progression. Our findings confirmed P. gingivalis presence in periodontitis tissue, with intracellular P. gingivalis mainly located in macrophages. However, P. gingivalis cannot be completely cleared by macrophages and enters the blood circulation through damaged periodontal tissue, leading to systemic infection. Transcriptomic analysis identified mitochondrial calcium uniporter (MCU) as a potential key molecule associated with P. gingivalis immune evasion in macrophages. In vitro functional analyses further confirmed that P. gingivalis infection increased MCU expression and led to both cytosolic and mitochondrial calcium overload, thereby impairing intracellular P. gingivalis clearance in macrophages. Notably, as a natural calcium antagonist, magnesium could inhibit the MCU pathway, reverse calcium overload, and enhance the macrophage‐mediated P. gingivalis clearance. Local administration of magnesium‐containing alginate methacryloyl (AlgMA) hydrogel significantly reduced both local and systemic P. gingivalis infection, relieved inflammation, and alleviated periodontal tissue destruction. Collectively, our findings identify MCU‐mediated calcium overload as a previously unrecognized mechanism by which P. gingivalis evades macrophage immune clearance. Moreover, magnesium‐mediated restoration of Ca 2+ homeostasis offers a promising host‐directed immunomodulatory therapy for periodontitis and other infectious diseases.