2026-06-30 | Inhibition of the Caspase-9/GSDME axis by Auranofin: a potential therapeutic strategy for bacterial toxin-mediated severe systemic disease
Bacterial toxin-mediated severe systemic diseases, such as Shiga toxin-induced hemolytic uremic syndrome (HUS), are associated with an exceptionally high mortality rate due to life-threatening multi-organ failure and a profound inflammatory surge. Despite this severe clinical burden, targeted therapeutic drugs remain unavailable. Here, we investigated the therapeutic potential of Auranofin (AUR), an FDA-approved compound, in mitigating systemic lethality by targeting the Caspase-9/GSDME-mediated cell death axis. Utilizing a high-throughput screening of 2819 FDA-approved drugs, we identified AUR as a potent inhibitor of Stx2-induced cytotoxicity in THP-1 macrophages. In vitro, AUR pre-treatment (2.5 μM) significantly preserved cell viability, stabilized mitochondrial membrane potential, and suppressed the release of pro-inflammatory IL-1β and LDH. Mechanistic analysis revealed that AUR abrogated the activation of Caspase-9 and Caspase-3, effectively blocking GSDME-mediated pyroptosis. In a C57BL/6 mouse model of Stx2-induced systemic injury, AUR administration significantly prolonged survival time and ameliorated renal and intestinal dysfunction. Histological evaluation confirmed that AUR reduced renal tubular necrosis, fibrin deposition, and the infiltration of macrophages and neutrophils. Western blot analysis of kidney tissues further corroborated the inhibition of the Caspase-9/GSDME axis in vivo. Our findings elucidate that AUR represents a promising drug-repurposing strategy for treating severe systemic syndromes by intercepting the crosstalk between apoptosis and pyroptosis, highlighting a novel, translational therapeutic paradigm for acute toxemia.
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2026-06-29 | N-Acetyl-L-Cysteine as a Potential Adjunctive Strategy in STEC-HUS: Mechanistic Rationale and Current Evidence
Shiga toxin-producing Escherichia coli (STEC) infections are a major cause of hemolytic uremic syndrome (HUS), a thrombotic microangiopathy characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The pathogenesis of STEC-HUS is primarily driven by Shiga toxins (Stx), which induce endothelial injury, inflammation, platelet activation, and microvascular thrombosis. Hemolysis associated with thrombotic microangiopathy leads to the release of hemoglobin and free heme into the circulation. Free heme, an iron-containing molecule with potent pro-oxidative, pro-inflammatory, and cytotoxic properties, contributes to oxidative stress, endothelial dysfunction, complement activation, and further tissue injury. Oxidative stress plays a crucial role in both host and bacterial cells, influencing disease progression and the expression of bacterial virulence factors, including Shiga toxin. N-acetyl-L-cysteine (NAC), a precursor of glutathione (GSH) and a well-established antioxidant, has attracted attention as a potential adjunctive therapeutic agent due to its antioxidant, anti-inflammatory, antiplatelet, and cytoprotective properties. In addition, NAC may influence iron- and heme-mediated oxidative damage and improve erythrocyte resistance to oxidative stress. This review summarizes current knowledge regarding the roles of oxidative stress and free heme in STEC-HUS and examines the mechanistic rationale and current evidence supporting NAC as a potential adjunctive strategy. The available evidence remains largely indirect and preclinical; therefore, the potential role of NAC in STEC-HUS should be considered hypothesis-generating and requires further investigation in clinical studies.
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2026-06-26 | Protection of Mice Orally Infected With Shiga Toxin-Producing Citrobacter rodentium Treated With Nanobody Multimer.
Shiga toxin (Stx)-producing Escherichia coli (STEC) colonizes the gut and causes enteritis through bacterial attachment-effacement (A/E), leading to mucosal damage. This facilitates systemic uptake of Stx, which can often lead to hemolytic-uremic syndrome (HUS) and acute renal failure, particularly in children <5 years of age. STEC infections expressing Stx2 variants are a major risk factor for HUS. Beyond patients receiving supportive care, there is no treatment for STEC-mediated HUS, and antibiotics are contraindicated. The 3- to 7-day prodromal interval between onset of STEC diarrhea and HUS offers a window for intervention for diarrheic patients, contacts thereof, or individuals exposed to the source of infection. Citrobacter rodentium (Cr), a mouse pathogen that exhibits mucosal bacterial A/E, was genetically constructed to express Stx2d (Cr-Stx2d). This, along with a Cr parent strain carrying the kanamycin gene, were used to model STEC in mice. Mice were treated intraperitoneally with a broad subtype-specific, Stx-neutralizing nanobody multimer fused to the human IgG1 Fc domain (VNA2-Stx/hFc). When a single treatment was administered as late as 4 days after Cr-Stx2d challenge, likely within the human STEC-HUS window of intervention, complete protection of mice was achieved. This Cr-Stx2d model, which mimics elements of human STEC infections by causing mucosal gut lesions and systemic Stx2d-mediated kidney damage, will help evaluate specific treatments against STEC-HUS, as demonstrated here with VNA2-Stx/hFc-treated mice given a single injection well after bacterial challenge. This product should be safe, simple, and economical to manufacture.
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