Thioredoxin attenuates ischemia-reperfusion-induced pressure ulcer formation by enhancing HIF-1α/BNIP3-dependent mitophagy and suppressing MAPK/NF-κB signaling.

Ischemia-reperfusion (I/R) injury plays a pivotal role in the pathogenesis of pressure ulcer formation. In I/R microenvironments, mitophagy serves as an essential cellular self-protection mechanism for clearing damaged mitochondria and preventing apoptosis and inflammatory responses; the HIF-1α/BNIP3 signaling pathway acts as the central hub regulating this process. Thioredoxin (TRX), a critical redox-regulatory protein, has shown protective effects in I/R-related diseases, but its role in cutaneous I/R injury remains unclear. In this study, we investigated whether recombinant human TRX (rhTRX) alleviates I/R-induced skin injury and explored the underlying mechanisms using a murine pressure ulcer model and an in vitro keratinocyte I/R model. rhTRX treatment significantly reduced tissue damage, neutrophil infiltration, and the levels of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6), the oxidative stress marker 8-OHdG, and apoptosis-related proteins (BAX, cleaved caspase-3), while increasing BCL-2 expression. Mechanistically, rhTRX suppressed intracellular ROS production and increased GSH level, it also inhibited MAPK/NF-κB signaling, thereby attenuating mitochondria-mediated inflammation and apoptosis. In addition, rhTRX preserved mitochondrial integrity by reducing cytochrome c and mitochondrial DNA release. Notably, rhTRX enhanced HIF-1α/BNIP3/LC3II-dependent mitophagy, and HIF-1α silencing partially abolished these protective effects. In conclusion, rhTRX mitigates cutaneous I/R injury by reducing oxidative stress and inflammation and by promoting mitophagy-mediated mitochondrial quality control. These findings suggest that topical TRX represents a potential therapeutic strategy for pressure ulcer prevention and treatment.