Magnesium sulfate attenuates sepsis-induced myocardial injury through macrophage Fxyd2/NF-κB signaling: Integrated evidence from a propensity-matched cohort, single-cell atlas, and mechanistic validation

BACKGROUND Sepsis-induced myocardial injury (SIMI) affects approximately 20%-55% of septic patients, with associated mortality ranging from 37% to 70%; however, evidence for magnesium sulfate (MgSO₄) as a targeted SIMI intervention and its molecular basis remain poorly defined. METHODS We integrated three evidentiary levels. A retrospective cohort of 2219 SIMI patients from the MIMIC-IV database underwent 1:1 propensity score matching (PSM; n = 992) and piecewise Cox regression (Day 10 landmark) to evaluate 28-day mortality. Single-cell RNA sequencing (scRNA-seq) of murine septic cardiac tissue characterized immune dynamics and identified MgSO₄-responsive targets. A macrophage-cardiomyocyte conditioned-medium transfer model, supplemented by Western blotting, RT-qPCR, and pyroptosis assays, validated the Fxyd2/NF-κB axis. RESULTS MgSO₄ conferred robust survival benefit during the acute phase (Days 0-10; aHR = 0.402, 95% CI: 0.302-0.536, P < 0.001), representing a 59.8% relative risk reduction. The benefit was independent of baseline serum magnesium, indicating a pharmacological rather than nutritional effect. scRNA-seq revealed MgSO₄ enriched reparative macrophage subsets via mineral absorption pathways, identifying Fxyd2 as a key responsive gene. In vitro, MgSO₄ pretreatment remodeled the macrophage secretome-suppressing TNF-α, IL-6, and MCP-1-thereby abrogating paracrine NLRP3-caspase-1-GSDMD pyroptosis in H9c2 cardiomyocytes. Mechanistically, MgSO₄ preserved FXYD2 expression in LPS-stimulated macrophages, inhibiting NF-κB phosphorylation and downstream pro-inflammatory transcription. CONCLUSIONS MgSO₄ provides time-dependent cardioprotection in SIMI by reprogramming the macrophage secretome via the Fxyd2/NF-κB axis, repositioning it as a targeted immunomodulatory agent and providing rationale for early administration in future randomized trials.