ADH7 and plasma proteins mediate smoking-related esophageal cancer: genetic causality and therapeutic insight.

Background: Smoking has been linked to alterations in plasma protein profiles and increased risk of esophageal cancer (EC). However, the precise mediating roles of plasma proteins in this relationship remain unclear. This study explores the mediation effects of plasma proteins in smoking-associated EC, utilizing genetic proxies to uncover potential biological mechanisms underpinning this association. Methods: Genetic correlation and Mendelian randomization (MR) analyses were applied to examine the association between smoking traits and EC. Pathway enrichment analysis explored circulatory protein changes in smokers. A two-step mediation MR analysis identified key plasma proteins involved in smoking-related EC pathogenesis. Survival analysis assessed the impact of transcriptional levels of mediators on EC prognosis, while phenome-wide association studies (PheWAS) evaluated the safety of targeted molecules and investigated potential pleiotropy. The expression and function of ADH7 were evaluated by qRT-PCR and Results: Genetic correlation analysis showed significant links between smoking and EC, supported by MR findings that confirmed a causal relationship. Smoking was found to influence pathways related to cytokine signaling, immune activation, and the STAT pathway. Five plasma proteins (ADH7, CPXM1, FUT3, GZMM, LYPD3) were identified as mediators in smoking-driven EC risk. Among these, ADH7 emerged as a key protein and was consistently associated with smoking traits; high ADH7 mRNA expression in EC tumor tissue was associated with reduced progression-free survival. PheWAS inferred that ADH7-targeted interventions might pose risks of neurological or psychiatric side effects, though these were not statistically significant. qRT-PCR and immunohistochemistry showed that ADH7 was downregulated in EC tissues relative to adjacent normal mucosa, and functional assays demonstrated that overexpression of ADH7 suppressed the proliferative and migratory capacity of EC cells. Serum ELISA further revealed that circulating ADH7 concentrations were elevated in smokers and in EC patients, with the highest levels observed in smoking EC patients, supporting a role for smoking-driven elevation of circulating ADH7 in EC risk. Conclusions: This study reveals a compartment-specific, dual role for ADH7 in smoking-related EC: elevated circulating ADH7, driven in part by smoking, is associated with increased EC risk, whereas ADH7 acts as a tumor suppressor within esophageal tumor tissue. These findings provide novel genetic and mechanistic insights into smoking-related EC pathogenesis and highlight the importance of distinguishing circulating from tissue-level protein function when interpreting biomarker-disease associations.