PM2.5 promotes lung cancer progression by upregulating CTSL to relieve autophagic flux blockade and enhance the malignant cellular phenotype.

Ambient fine particulate matter (PM2.5) has been widely confirmed to severely threaten human health and is closely associated with the development and progression of respiratory diseases such as chronic obstructive pulmonary disease, pulmonary fibrosis, and lung cancer. This study aimed to investigate the key molecular targets and mechanisms by which PM2.5 induces lung cancer progression. Using an in vitro model, A549 cells were exposed to different concentrations of PM2.5 for 48 h. PM2.5 treatment significantly reduced cell proliferation, migration, and invasion, while increasing apoptosis. It also led to substantial reactive oxygen species (ROS) accumulation, impaired mitochondrial and lysosomal function, and abnormally enhanced autophagy. RNA-seq and RT-qPCR revealed that PM2.5 significantly upregulated cathepsin L (CTSL) expression, which correlated with the expression of autophagy-related genes p62/SQSTM1 and LC3B. Functional assays showed that CTSL overexpression further enhanced PM2.5-induced autophagic activity and promoted autophagic degradation, thereby promoting the malignant phenotype of A549 cells. Conversely, CTSL knockdown impaired autophagic degradation, reduced cell invasion, and aggravated cellular damage. These results suggest that PM2.5 promotes malignant transformation of A549 cells by upregulating CTSL and modulating autophagic homeostasis. In vivo experiments using an orthotopic mouse model confirmed the tumor-promoting role of CTSL and revealed that chronic PM2.5 exposure significantly promotes lung cancer growth within the tumor microenvironment. In conclusion, CTSL is a key molecular target in PM2.5-driven lung cancer progression. Targeting CTSL may offer new strategies for preventing and treating PM2.5-associated lung cancer and provide important theoretical insights into how environmental exposure factors drive tumor development.