Ferroptosis in smoke inhalation injury: from mechanisms to potential therapeutic targets

Smoke inhalation injury (SII) is a prevalent yet underrecognized cause of acute respiratory failure and longer-term airway-alveolar remodeling after fires, wildfires, and industrial accidents. Beyond inflammation and generic oxidative stress, accumulating evidence supports ferroptosis as a mechanistically distinct, self-amplifying axis that can sustain epithelial/endothelial damage, barrier breakdown, and maladaptive repair. Ferroptosis is driven by iron-dependent phospholipid peroxidation and collapse of membrane redox homeostasis, and in SII is promoted by iron dyshomeostasis including heme/hemoglobin-derived iron and ferritinophagy, PUFA-phospholipid remodeling, and failure of antioxidant checkpoints centered on the System Xc − -GSH-GPX4 pathway, with complementary protection via FSP1-CoQ10 and related radical-trapping systems. Despite rapid progress, how ferroptotic signaling integrates with other regulated cell-death programs and inflammatory circuits across the temporal phases of SII remains incompletely defined. In this review, we synthesize molecular mechanisms, crosstalk networks, candidate biomarkers, and preclinical evidence for therapeutically actionable nodes, highlighting ferroptosis inhibitors, iron-targeting approaches, and redox-restorative strategies as candidates for mechanism-guided, disease-modifying intervention in SII.