Lung cancer is a commonly diagnosed disease worldwide, with non‐small cell lung cancers (NSCLCs) accounting for ≈ 85% of cases. Cigarette smoke is an environmental exposure promoting progression of NSCLC, but its role is poorly understood. This study reports that smoking‐induced accumulation of M2‐type tumor‐associated macrophages (M2‐TAMs) surrounding NSCLC tissues promotes malignancy. Specifically, extracellular vesicles (EVs) from cigarette smoke extract (CSE)‐induced M2 macrophages promoted malignancy of NSCLC cells in vitro and in vivo. circEML4 in EVs from CSE‐induced M2 macrophages is transported to NSCLC cells, where it reduced the distribution of ALKBH5 in the nucleus by interacting with Human AlkB homolog H5 (ALKBH5), resulting in elevated N6‐methyladenosine (m6A) modifications. m6A‐seq and RNA‐seq revealed suppressor of cytokine signaling 2 (SOCS2)‐mediated activation of the Janus kinase‐signal transducer and activator of transcription (JAK‐STAT) pathway by regulating m6A modification of SOCS2 via ALKBH5. Down‐regulation of circEML4 in EVs from CSE‐induced M2 macrophages reversed EVs‐enhanced tumorigenicity and metastasis in NSCLC cells. Furthermore, this study found that smoking patients showed an increase in circEML4‐positive M2‐TAMs. These results indicate that smoking‐induced M2‐TAMs via circEML4 in EVs promote the NSCLC progression through ALKBH5‐regulated m6A modification of SOCS2. This study also reveals that circEML4 in EVs from TAMs acts as a diagnostic biomarker for NSCLC, especially for patients with smoking history.

Arsenic is a recognized environmental pollutant naturally occurring in aquifers through geological processes. Toxicological studies have revealed that liver is the main target organ harmed by arsenic exposure. However, systematic studies of non-alcoholic fatty liver disease (NAFLD) are not comprehensive, and information regarding threats and risk assessment remains insufficient. This research aimed to examine the association between arsenic exposure and NAFLD and uncover the role of molecular initiating events and key events in disease development using the Adverse Outcome Pathway (AOP). Data from 8,104 adults in the National Health and Nutrition Examination Survey were used to explore the relationship between urinary arsenic and NAFLD. In a logistic regression model, urinary inorganic arsenic levels positively correlated with NAFLD (odds ratio = 1.12, 95 % confidence interval = 1.07-1.16). Subsequently, to gain a deeper understanding of arsenic-induced NAFLD, an AOP framework was constructed, revealing that arsenic exposure led to elevate levels of TNF-α, which regulated the NF-κB pathway and led to hepatic lipid deposition, causing NAFLD. This AOP was assessed as "high" according to the Organization for Economic Co-operation and Development users' handbook, and in vitro and in vivo models validated the AOP framework. In summary, this study highlights the potential mechanisms of arsenic-induced NAFLD. We combined the AOP with classical toxicological approaches with a view of establishing, rapidly and accurately, the lowest level at which environmental arsenic exposure can have adverse effects on the body, thereby contributing to risk assessment strategies for arsenic exposure through iterative and animal modeling at the population level.