Sulfhydrated TFEB alleviates blast-induced lung injury by maintaining epithelial barrier integrity through the IGF2R/MMP-2/9 pathway.

Blast-induced lung injury (BLI) is a life-threatening complication of explosive shock waves, yet its molecular mechanisms remain largely unclear. This study aimed to elucidate the key molecular mechanisms governing epithelial barrier integrity during BLI progression and define the core regulatory function of Transcription Factor EB (TFEB) and its downstream signaling axis in BLI pathogenesis. We also evaluated the therapeutic effect and underlying mechanism of the hydrogen sulfide (H2S)-releasing nanozyme (Pt@Pd-S), intending to offer novel targets and translational therapeutic strategies for BLI. Bioinformatic analysis of single-cell RNA sequencing (scRNA-seq) data revealed activation of adherens junction, tight junction, and multiple stress-related signaling pathways in epithelial cells. Transcription factor analysis identified TFEB as a pivotal regulator in these pathological processes. Functional experiments demonstrated that TFEB overexpression via lentiviral delivery significantly alleviated BLI, as evidenced by reduced pulmonary edema, inflammation, oxidative stress and improved barrier integrity. Insulin-like growth factor 2 receptor (IGF2R) was identified as a novel target of TFEB and participates in the protection against shock wave-induced epithelial barrier damage by regulating the release of matrix metallopeptidase 2 (MMP-2) and matrix metallopeptidase 9 (MMP-9). Furthermore, the Pt@Pd-S nanozyme promoted S-sulfhydration of TFEB at the Cys212 residue, thereby enhancing its transcriptional activity, upregulating autophagy, improving lysosomal function, and maintaining epithelial barrier integrity and mitigating lung injury through modulating the IGF2R/MMP-2/9 signaling pathway. Collectively, our findings uncover a previously unrecognized TFEB/IGF2R/MMP-2/9-autophagy and lysosomal axis in the pathogenesis of BLI and highlight the promise of engineered H2S-releasing nanozymes as a therapeutic strategy for pulmonary trauma.