Pharmacovigilance study and genetic target prediction analysis of FDA adverse event reporting system for anticancer drug-associated interstitial lung disease.

Anticancer drug-associated interstitial lung disease (ILD) is a serious adverse event. Identifying high-risk drugs and elucidating pathogenic mechanisms are crucial for prevention and management. Based on 21 years of the US Food and Drug Administration Adverse Event Reporting System (FAERS) data, we identified anticancer drugs strongly associated with ILD in solid tumor patients using disproportionality analysis and logistic regression. Network pharmacology identified overlapping targets between anticancer drugs and ILD. Mendelian randomization (MR) was used to assess causal links between target gene/protein expression and ILD. Molecular docking further evaluated drug-target binding. Finally, mediation MR analysis was applied to assess the role of immune cells and metabolites in mediating the causal effect of CD40 on ILD. We identified 21 anticancer drugs as independent risk factors for ILD, with the majority exhibiting an early failure mode. ILD onset was primarily observed within the first three months. Network pharmacology and MR analyses pinpointed CD40 as a key pathogenic target. Elevated CD40 expression causally increased ILD risk. Molecular docking further confirmed stable binding between gemcitabine and CD40. Mediation MR revealed CD40 influences ILD risk via specific Tregs (CD28 on secreting Treg, CD28 on activated & secreting Treg, and CD28 on CD45RA⁻ CD4 non-Treg) and metabolites (gamma-glutamylvaline, S-adenosylhomocysteine (SAH) to 5-methyluridine ratio). This integrated study reveals CD40 as a key contributor to anticancer drug-associated ILD, especially linked to gemcitabine. CD40 exerts its effect through dysregulation of specific Tregs and metabolites. These findings reveal novel disease mechanisms and identify potential therapeutic targets, providing new clues for the prevention and treatment of anticancer drug-associated ILD.