Glycyrrhizin alleviates Mycoplasma pneumoniae-induced acute lung injury in mice by regulating ferroptosis via the GPX4/ACSL4 axis.
AI interpretation is pending for this paper.
Open original publication →What the AI sees
Not AI summarized yet.
Research significance
Pending deeper interpretation.
Source abstract
BACKGROUND: Mycoplasma pneumoniae (MP) is a major cause of community-acquired pneumonia in children and can induce severe acute lung injury (ALI). Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, remains poorly understood in MP-induced ALI. Glycyrrhizin possesses anti-inflammatory and antioxidant properties, but its potential to alleviate MP-associated ALI via ferroptosis modulation has not yet been established. This study investigated the role of ferroptosis in MP-induced ALI and evaluated the therapeutic efficacy and underlying molecular mechanisms of glycyrrhizin in a murine model. METHODS: Forty specific pathogen-free male BALB/c (Bagg albino substrain c) mice (4-5 weeks old, 20±2 g) were randomly assigned to five experimental groups (n=8 per group): control, MP-low, MP-high, MP-high + ferrostatin-1 (Fer-1, a specific ferroptosis inhibitor), and MP-high + glycyrrhizin. The MP infection model was established via intranasal instillation for three consecutive days. On day 7 post-instillation, lung histopathology, bronchoalveolar lavage fluid (BALF) inflammatory profiles, pro-inflammatory cytokines [interleukin (IL)-6, tumor necrosis factor-α (TNF-α), IL-1β, interferon-gamma (IFN-γ)], oxidative stress markers [malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), reduced glutathione to oxidized glutathione (GSH/GSSG) ratio], tissue iron content, and ferroptosis-regulatory proteins (GPX4, ACSL4, HMGB1) were systematically evaluated. RESULTS: The MP-low group induced only mild pulmonary changes with no statistically significant alterations in inflammatory or ferroptotic biomarkers compared to the control group (P>0.05). Conversely, the MP-high group caused severe ALI, characterized by markedly elevated BALF inflammatory cell infiltration and cytokine secretion (2.3- to 3.8-fold), increased tissue concentrations of MDA, 4-HNE, and ferrous iron (Fe2+; 1.8- to 2.5-fold), a 61% reduction in the GSH/GSSG ratio, a 62% downregulation of GPX4, and a 2.1-fold upregulation of ACSL4 (all P<0.05 versus the control group). Glycyrrhizin intervention significantly attenuated these pathological changes: the histopathological lung injury score decreased by 54%, pro-inflammatory cytokine levels fell by 42% to 67%, lipid peroxidation markers decreased by 45% to 52%, the GSH/GSSG ratio increased 1.6-fold, GPX4 expression was rescued 1.7-fold, and ACSL4 expression was suppressed by 58% (all P<0.05 versus the vehicle-treated MP-high group). Crucially, the tissue-protective and anti-ferroptotic effects of glycyrrhizin were comparable to those of the positive control, Fer-1 (P>0.05). CONCLUSIONS: Ferroptosis serves as a substantial pathological driver of MP-induced ALI. Glycyrrhizin effectively mitigates severe lung injury by inhibiting pulmonary ferroptosis through the modulation of the GPX4/ACSL4 axis and by suppressing secondary inflammatory cascades. These findings provide a novel mechanistic insight and an experimental therapeutic rationale for treating severe MP-associated respiratory complications in pediatric clinical settings.