PM2.5 can cause lung cell injury. Due to the complexity and variation of the physical and chemical properties of PM2.5, the risk of lung cell injury may depend significantly on the type of atmospheric environment. With a population of 120 million, the Chengdu-Chongqing region in China is the most populated region in the world that experiences both high humidity and low solar radiation (HHLR). However, PM2.5-related lung cell injury and treatment strategies in this type of environment are still unclear. Thus, our study focuses on the relationships between the chemical components, lung cell injury effects, and pathogenic mechanisms of PM2.5 in HHLR (HHLR-PM2.5). In terms of mass, organic carbon (OC), NO3−, SO42−, and NH4+ are found to be the most significant components of HHLR-PM2.5. Extracts of HHLR-PM2.5 significantly inhibit cell viability, stimulate reactive oxygen species (ROS) levels, and trigger inflammation. Utilizing a combination of multi-omics, bioinformatics, and molecular biology, it is found that HHLR-PM2.5 extracts inhibit E3 ubiquitin-protein ligase (UHRF1) to suppress DNA methyltransferase 1 (DNMT1) and hamper DNA methylation, culminating in lung cell injury. Additionally, integrating transcriptomic data with human disease databases highlights chronic obstructive pulmonary disease (COPD) as a potential lung cell injury-related respiratory affliction induced by HHLR-PM2.5. This study expands the scientific comprehension of the health risks associated with HHLR-PM2.5, deciphers the molecular mechanism of lung cell injury, and provides precise treatment strategies for HHLR-PM2.5-induced lung cell injury.