Chronic PPDs/6PPDQ exposure triggers lung injury via MDM2 binding-mediated p53 accumulation and PI3K-AKT signaling...

P-phenylenediamines (PPDs) and their quinone derivatives (PPDQs) are widely employed as antioxidants in the manufacturing of rubber products. Their pervasive environmental distribution has led to widespread human exposure, raising concerns about respiratory health. While pulmonary toxicity has been reported, the molecular mechanisms underlying lung injury induced by chronic low-dose co-exposure to multiple PPDs/PPDQs congeners remain unclear. Here, we selected five environmentally prevalent PPDs (6PPD, 77PD, CPPD, DPPD, and IPPD) alongside 6PPDQ, and integrated network toxicology, molecular docking, in vivo and in vitro experiments, and transcriptomic profiling to investigate the common molecular targets and signaling pathways. Our findings demonstrated that PPDs/6PPDQ bound to the p53-binding domain of MDM2, thereby blocking MDM2-mediated p53 degradation and resulting in persistent p53 protein accumulation. Under chronic stress, sustained p53 elevation was functionally associated with downregulation of the PI3K-AKT signaling pathway, which drove cellular senescence and senescence-associated secretory phenotype (SASP), promoted a pro-inflammatory microenvironment, and ultimately disrupted pulmonary epithelial barrier integrity. Despite limited overlap at the gene level, both network toxicology and transcriptomic analyses converged on the PI3K-AKT pathway as the key signaling axis. This study revealed the core regulatory role of the MDM2-p53 axis and its crosstalk with the PI3K-AKT signaling pathway in PPDs/6PPDQ-induced lung injury, providing new mechanistic insights for the prevention and intervention of respiratory diseases associated with environmental pollutants.