An increasing number of researches have shown that fine particulate matter (PM2.5) is closely related to increased respiratory inflammation and can even lead to lung cancer. Estrogen receptor β (ERβ) has been demonstrated to be involved in several cancers. However, the exact role of ERβ in PM2.5 organic extract (Po)-promoted inflammation and lung cancer remains unknown. The purpose of this study was to investigate whether ERβ is involved in Po induced inflammation and lung cancer. In vitro, our results showed that interleukin-6 (IL-6) and ERβ were simultaneously increased in lung bronchial epithelial cells exposed to Po; additionally, inhibition of ERβ decreased IL-6 expression and secretion through inactivating ERK and AKT and further promoted cells malignant transformation. Moreover, we performed an animal model of inhalation exposure to Po using female C57BL/6 mice. Although we were unable to find tumor tissue in mice exposed to Po, we detected evidence of lung inflammation, epithelial-to-mesenchymal transition (EMT) phenotype and severe pulmonary injury; in addition, intraperitoneal injection of PHTPP (an ERβ inhibitor) showed that the above phenomena have been improved, which demonstrate that Po stimulates IL-6 expression to promote inflammation, EMT phenotype and lung injury through the ERβ pathway. In conclusion, our results confirmed the potential toxic effect of PM2.5, and increased our understanding of PM2.5 carcinogenic potential by exploring the mechanism of ERβ regulating inflammation.Copyright © 2020 Elsevier Ltd. All rights reserved.