Coal Dust‐Mimetic Carbon Nanoparticles Induce Colonic Epithelial Cell Senescence via p16/p21 Dual Pathways and Promote Colonic Inflammatory Response

BACKGROUND AND AIM: The incidence of inflammatory bowel disease among coal miners is globally higher than that in the general population; however, the underlying pathogenic mechanisms remain unclear. Given that the composition and particle size of coal dust are key determinants of its toxicity, this study investigates the pathogenic role and molecular mechanism of coal dust-mimetic carbon nanoparticles (CNPs) in inflammatory bowel disease. METHODS: In this study, an in vivo exposure rat model was established by intranasal instillation of CNPs for 4, 8, and 12 weeks. Combined with transcriptomic sequencing as well as in vivo and in vitro experiments, relevant indicators of mitochondrial damage and cellular senescence were systematically evaluated. RESULTS: Rats intranasally administered with CNPs exhibited sustained decreases in daily weight gain, elevated spleen index, along with colonic pathological damage, inflammatory responses, impaired intestinal barrier function, and gut microbiota dysbiosis. Furthermore, in vitro and in vivo, incorporating transcriptomic sequencing and experimental research have confirmed that CNP exposure induces mitochondrial damage, evident from enriched mitochondrial damage signals, altered mitochondrial morphology and structure, increased reactive oxygen species levels, and reduced mitochondrial membrane potential. Simultaneously, cellular senescence is triggered, including cell cycle arrest, suppressed transcriptional activity, reduced cell proliferation capacity, and marked activation of the p16/p21 dual signaling pathway. CONCLUSIONS: These findings suggest that the simultaneous enrichment of mitochondrial damage signals and cellular senescence phenotypes may be a core event in CNP-induced colitis, with the p16/p21 dual signal acting as the "molecular switch" regulating this process. Targeting and inhibiting the p16/p21 dual signaling pathway may offer a novel strategy for preventing and treating colitis induced by coal dust exposure in coal miners.