The FDA-approved excipient N,N-dimethylacetamide improves survival and attenuates inflammatory pathways in a murine model of endotoxemia

Abstract

Sepsis is a life-threatening organ dysfunction resulting from a dysregulated host response to infection and remains a major public health burden. According to the Centers for Disease Control and Prevention, approximately 1.7 million adults in the United States develop sepsis annually. We previously demonstrated that the United States Food and Drug Administration–approved drug excipient N,N-dimethylacetamide (DMA) suppresses inflammatory responses through inhibition of the nuclear factor kappa B (NF-κB) pathway. In the present study, DMA completely prevented mortality in a murine model of acute (24 h) moderate endotoxemia and significantly improved survival in acute severe endotoxemia. In mice with severe endotoxemia, serum interleukin-6 (IL-6) and tumor necrosis factor–α (TNF-α) levels were significantly reduced in DMA-treated animals compared with lipopolysaccharide (LPS)-only controls. In long-term (96 h) moderate endotoxemia, pretreatment with DMA significantly improved clinical parameters, including mobility, heart rate, and respiratory rate. In the liver, DMA suppressed LPS-induced expression of pro-inflammatory cytokines and acute-phase proteins, enhanced expression of the anti-inflammatory cytokine IL-10, attenuated NLRP3 inflammasome activation, and modulated leukocyte infiltration in pretreated mice. In U937 macrophages, DMA inhibited LPS-induced release of IL-6 and TNF-α. Notably, macrophages differentiated in the presence of DMA exhibited an attenuated inflammatory response to subsequent LPS stimulation. Collectively, these findings identify DMA as a promising adjunctive therapeutic anti-inflammatory candidate in endotoxemia that warrants further evaluation in clinically relevant models of sepsis.

Introduction

Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection, resulting in life-threatening organ dysfunction [1]. Despite advances in critical care, sepsis remains a leading cause of morbidity and mortality worldwide. In the United States alone, an estimated 1.7 million adults develop sepsis each year, and approximately 350,000 die during hospitalization or are discharged to hospice care [2]. Septic shock, defined by vasopressor-dependent hypotension and elevated lactate levels despite adequate fluid resuscitation, is associated with particularly high mortality [1]. Current treatment strategies remain largely supportive—centered on infection control, hemodynamic stabilization, and organ support—while no approved pharmacologic therapy directly targets the dysregulated inflammatory cascade that drives sepsis pathogenesis [3], [4]. Numerous anti-cytokine, antioxidant, and immunomodulatory approaches have failed to yield meaningful clinical benefit, underscoring the urgent need for safe, mechanism-based therapeutic agents [5], [6].

N,N-dimethylacetamide (DMA) is an FDA-approved excipient widely used as a solvent in clinical drug formulations, including busulfan and teniposide [7], [8], [9]. Although long regarded as pharmacologically inert, we and others identified DMA as a previously unrecognized small-molecule inhibitor of nuclear factor κB (NF-κB) signaling with potent anti-inflammatory and immunomodulatory activity [10], [11], [12]. Our prior work demonstrated that DMA suppresses LPS- and TNFα-induced production of proinflammatory mediators—including IL-6, TNFα, CCL2, and HMGB1—attenuates oxidative and nitrosative stress and reduces leukocyte infiltration and tissue injury in diverse inflammatory settings [10], [12], [13]. DMA also alleviates preterm birth–associated inflammation, mitigates colitis, and diminishes neuroinflammation by suppressing NF-κB–dependent cytokine expression and amyloid β precursor protein production in microglial cells [10], [13], [14], [15], [16]. These findings establish DMA as a clinically accessible small molecule with broad anti-inflammatory efficacy and a well-characterized safety profile.

Given the central role of NF-κB activation in sepsis pathophysiology and the established anti-inflammatory actions of DMA, we hypothesized that DMA could confer therapeutic protection in sepsis by suppressing NF-κB–driven inflammatory signaling. Here, we report that DMA treatment significantly improves survival in LPS-induced murine endotoxemia, accompanied by a marked reduction in circulating proinflammatory cytokines, attenuation of hepatic injury, and preservation of tissue architecture. These findings provide compelling preclinical evidence that repurposing DMA—an FDA-approved excipient with newly discovered NF-κB–inhibitory activity—represents a promising and translationally feasible strategy for the treatment of sepsis and related inflammatory diseases.

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Zhihui Xiao, Sean Carrig, Sandra E. Reznik, The FDA-approved excipient N,N-dimethylacetamide improves survival and attenuates inflammatory pathways in a murine model of endotoxemia, Biomedicine & Pharmacotherapy, Volume 199, 2026, 119403, ISSN 0753-3322, https://doi.org/10.1016/j.biopha.2026.119403.