Mechanism of macrophage mitochondrial transfer in CBNPs induced EndMT of pulmonary microvascular endothelial cells

Carbon black nanoparticles (CBNPs) have been identified as a potential contributing factor to idiopathic pulmonary fibrosis (IPF), though the specific mechanisms by which they induce endothelial-mesenchymal transition (EndMT) remain to be fully elucidated. The objective of this study was to ascertain whether CBNPs induce EndMT in pulmonary microvascular endothelial cells via PANoptosis-mediated mitochondrial transfer in alveolar macrophages (AMs). A mouse model of CBNPs inhalation exposure was established to evaluate pulmonary function, collagen deposition, and EndMT biomarkers. Co-culture systems of alveolar macrophages cells (M-HS) and pulmonary microvascular endothelial cells (MPVECs) were employed to investigate the process by which PANoptosis induced mitochondrial transfer. Key mechanisms were validated using Western blot, qPCR, molecular docking, co-immunoprecipitation, and bioinformatics analyses. The results showed that CBNPs exposure significantly impaired pulmonary function, induced collagen deposition, and activated EndMT. Conditioned media from CBNPs-treated M-HS triggered EndMT in MPVECs, mediated by the transfer of damaged mitochondria. Mechanistically, CBNPs suppressed the PINK1/Parkin mitophagy pathway, driving PANoptosis in M-HS and subsequent released of dysfunctional mitochondria. IFI27 was identified as a critical regulator of PANoptosis, directly binding to PINK1 to exacerbate mitochondrial dysfunction. Silencing IFI27 alleviated PANoptosis and mitochondrial transfer, reversing the EndMT phenotype in MPVECs. Collectively, these findings indicated that CBNPs induced EndMT in MPVECs via mitochondrial transfer, with the IFI27-PINK1 axis regulating this transfer process. This mitochondrial transfer represents as a novel therapeutic target for CBNPs-induced IPF. Moreover, modulating the process of mitochondrial transfer with IFI27 as a regulatory factor mitigate nanotoxicity-driven pulmonary fibrotic progression.