LPS-Induced Mitochondrial Damage via SLC41A1-Mediated Magnesium Ion Efflux Leads to the Pyroptosis of Dental Stem Cells

Although regenerative endodontics demonstrate promise for dental pulp regeneration, chronic inflammation often hinders the success. This study aims to explore the mechanism whereby lipopolysaccharide (LPS) induces dental pulp regeneration failure. Transcriptomic profiling of LPS-stimulated dental pulp stem cells (DPSCs) reveals dysregulated cation homeostasis and increased magnesium (Mg²⁺) transmembrane transport. Mechanistically, LPS is observed to activate the transcription factor signal transducer and activator of transcription 5A (STAT5A), which binds to the solute carrier family 41 member 1 (SLC41A1) promoter, thereby upregulating the Mg²⁺ efflux transporter and depleting intracellular Mg²⁺ levels. Mg²⁺ efflux destabilizes the mitochondrial permeability transition pore (mPTP), thus facilitating its opening via the interaction of oligomycin sensitivity-conferring protein (OSCP) and Cyclophilin D (CypD), which releases Reactive Oxygen Species (ROS) and mitochondrial DNA (mtDNA) and exacerbates oxidative stress. The released mtDNA activates the absent in melanoma 2 (AIM2) inflammasome, thereby amplifying gasdermin D (GSDMD)-mediated Pyroptosis. Exogenous supplementation with Mg²⁺ restores intracellular Mg²⁺ homeostasis, suppresses mPTP opening, and reduces mtDNA and ROS leakage, thereby rescuing DPSCs viability and differentiation capacity. This study identifies SLC41A1-mediated Mg²⁺ dysregulation as a pivotal driver of LPS-induced mitochondrial damage and demonstrates that Mg²⁺ replenishment is a therapeutic strategy to counteract inflammation-driven regenerative failure.

dental stem cell; magnesium ion; mitochondrial permeability transition pore; pyroptosis; solute carrier family 41 member 1.