Preclinical lung-injury study

Nicotinamide mononucleotide mitigates hyperoxia-aggravated septic lung injury via the GPx4-mediated anti-ferroptosis signaling pathway in alveolar epithelial cells

Ning Zhao et al. · Free Radical Biology and Medicine · 2025

Evidence type: Preclinical mechanistic study Interpretive weight: Mechanistic contextResearch area: Septic lung injury and ferroptosis
DesignPreclinical mechanistic study using a rat cecal-ligation-and-puncture sepsis model with hyperoxia plus alveolar epithelial cell experiments, ferroptosis modulation, SIRT6 modulation, and GPx4 knockdown.
PopulationRats with experimental sepsis-related lung injury and cultured alveolar epithelial cells exposed to LPS plus hyperoxia; no human participants.
SampleMultiple rat and cell experiments with sample sizes varying by experiment; the publication reports repeated intervention and mechanistic groups.
InterventionNMN treatment in hyperoxia-aggravated sepsis lung-injury models, alongside ferroptosis promoter/inhibitor, SIRT6 activator/inhibitor, and GPx4 knockdown conditions. Dose details vary across experimental components and should be interpreted from the methods rather than as a human-equivalent regimen.
EndpointsLung histological injury and wet/dry ratio; Oxygenation and inflammatory cytokines; Alveolar epithelial cell viability; Ferroptosis markers including Fe2+, MDA, ROS, GSH, ACSL4, GPx4, and 4-HNE; SIRT6 expression and dependence; Effect of GPx4 knockdown on NMN-associated protection

What the publication reported

This study examined NMN in experimental septic lung injury that was made worse by high oxygen exposure. The researchers used both a rat sepsis model and alveolar epithelial cells.

Hyperoxia increased lung injury, inflammation, oxidative stress, and ferroptosis-related changes. NMN attenuated several of these abnormalities, including restoring GPx4-related antioxidant defenses and lowering ferroptosis markers.

Mechanistic experiments suggested that NMN increased SIRT6, which in turn supported GPx4. Knocking down GPx4 or inhibiting SIRT6 weakened the protective pattern. These are preclinical findings and do not establish that NMN treats sepsis or ARDS in humans.

Key findings

  • Hyperoxia worsened experimental sepsis-related lung injury and increased ferroptosis-related damage.
  • NMN reduced histological injury, inflammatory signaling, and oxidative-stress markers in the reported models.
  • NMN increased GPx4 and GSH while reducing Fe2+, MDA, ROS, and ACSL4 in key experiments.
  • NMN increased SIRT6 expression in alveolar epithelial cells.
  • SIRT6 inhibition weakened GPx4 expression and worsened ferroptosis markers, while SIRT6 activation showed the opposite pattern.
  • GPx4 knockdown reversed much of the NMN-associated protection in the cell model.

What it cannot establish

  • The study used rat and cell models rather than patients with sepsis, ARDS, or hyperoxic lung injury.
  • Experimental hyperoxia and cecal-ligation-and-puncture conditions do not reproduce the full heterogeneity of human critical illness.
  • NMN dosing and route in experimental models cannot be translated directly to consumer oral supplementation.
  • The study focused on mechanistic and surrogate injury endpoints rather than patient-centered outcomes.
  • The proposed SIRT6/GPx4 pathway is strongly supported within the model but does not exclude additional mechanisms.
HealthspanX claim boundary: This study does not establish that NMN prevents or treats sepsis, ARDS, oxygen-related lung injury, or respiratory failure in humans.

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