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

Lipopolysaccharide induces upregulation of the magnesium (Mg2+) efflux transporter solute carrier family 41 member 1 in dental stem cells, leading to a decrease in intracellular Mg2+ concentration and promoting the binding of oligomycin sensitivity‐conferring protein and cyclophilinD. This enhances the sensitivity of mitochondrial permeability transition pore opening and triggers a cascade reaction that affects cell fate. Abstract 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. Lipopolysaccharide induces upregulation of the magnesium (Mg 2+ ) efflux transporter solute carrier family 41 member 1 in dental stem cells, leading to a decrease in intracellular Mg 2+ concentration and promoting the binding of oligomycin sensitivity-conferring protein and cyclophilinD. This enhances the sensitivity of mitochondrial permeability transition pore opening and triggers a cascade reaction that affects cell fate. Abstract 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 (Mg 2 ⁺) 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 Mg 2 ⁺ efflux transporter and depleting intracellular Mg 2 ⁺ levels. Mg 2 ⁺ 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 Mg 2 ⁺ restores intracellular Mg 2 ⁺ homeostasis, suppresses mPTP opening, and reduces mtDNA and ROS leakage, thereby rescuing DPSCs viability and differentiation capacity. This study identifies SLC41A1-mediated Mg 2 ⁺ dysregulation as a pivotal driver of LPS-induced mitochondrial damage and demonstrates that Mg 2 ⁺ replenishment is a therapeutic strategy to counteract inflammation-driven regenerative failure. Advanced Science, Volume 12, Issue 42, November 13, 2025.