Lps-Induced Mitochondrial Damage Via Slc41a1 Caused Pyroptosis Of Dpscs

Despite regenerative endodontic therapy holds promise for dental pulp revitalization, unresolved inflammatory microenvironments often hinder successful regeneration. This study aims to explore mechanism by which lipopolysaccharide (LPS)-induced dental pulp regenerative failure. Through transcriptome sequencing and bioinformatics analysis, changes in magnesium ion homeostasis were analyzed. Flow cytometry was used to analyze oxidative stress indicators, and molecular docking combined with immunoprecipitation was used to verify changes in protein binding ability. Transcriptomic profiling of LPS-stimulated dental pulp stem cells (DPSCs) revealed dysregulated cation homeostasis and enhanced magnesium (Mg²⁺) transmembrane transport. Mechanistically, LPS activates the transcription factor signal transducer and activator of transcription 5A (STAT5A), which directly binds to the solute carrier family 41 member 1 (SLC41A1) promoter, upregulating the Mg²⁺ efflux transporter and depleting intracellular Mg²⁺ levels. The Mg²⁺ efflux destabilizes mitochondrial permeability transition pore (mPTP), facilitating its opening via oligomycin sensitivity conferring protein (OSCP) and cyclophilin D (CypD) interaction, which releases reactive oxygen species (ROS) and mitochondrial DNA (mtDNA), exacerbating oxidative stress and membrane depolarization. Released mtDNA activates the absent in melanoma 2 (AIM2) inflammasome axis, amplifying gasdermin D (GSDMD) mediated pyroptosis and impairing DPSCs differentiation. Strikingly, exogenous Mg²⁺ supplement restored intracellular Mg²⁺ homeostasis, suppressed mPTP opening, and reduced mtDNA and ROS leakage. Our findings not only identify STAT5A / SLC41A1-mediated Mg²⁺ dysregulation as a pivotal driver of LPS-induced mitochondrial damage but also demonstrate Mg²⁺ replenishment as a therapeutic strategy to counteract inflammation-driven regenerative failure.