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Background  Lung adenocarcinoma (LUAD) is the main subtype of primary lung cancer and is a leading cause of cancer‐related death worldwide. PIWI‐interacting RNAs (piRNAs) are a type of small non‐coding RNAs that may play crucial roles in cancer progression and serve as biomarkers for tumor detection. This study aimed to explore the expression profiles and diagnostic values of piRNAs in LUAD.    Methods  Small RNA sequencing was performed to investigate tissue piRNA profiles of LUAD. The expression of selected upregulated piRNAs were detected in tissues and serum exosome samples by quantitative real‐time polymerase chain reaction (qRT‐PCR). Serum exosomes were identified by transmission electron microscope, nanoparticle tracking analysis, and western blot analysis. Receiver operating characteristic (ROC) curve was adopted to quantify the diagnostic potentials of piRNAs in LUAD. Finally, a piRNA panel was developed by multivariate logistic regression model.    Results  We identified that 76 piRNAs were overexpressed and 9 piRNAs were underexpressed in LUAD tissues compared with adjacent non‐tumor tissues. Among the top 10 overexpressed piRNAs, 4 piRNAs (piR‐hsa‐26925, piR‐hsa‐5444, piR‐hsa‐30636, and piR‐hsa‐8757) were verified by qRT‐PCR to be significantly upregulated in LUAD tissues. Moreover, piR‐hsa‐26925 and piR‐hsa‐5444 had a significantly higher level in serum exosome samples of LUAD patients than those of healthy controls. We finally established a 2‐piRNA panel composed of piR‐hsa‐26925 and piR‐hsa‐5444, which showed higher diagnostic performance for LUAD with an AUC of 0.833.    Conclusions  Our finding revealed the abnormally expressed piRNAs in LUAD, and serum exosomal piR‐hsa‐26925 and piR‐hsa‐5444 could serve as potential biomarkers for LUAD diagnosis.

PIWI ‐interacting RNAs are aberrantly expressed and may serve as novel biomarkers for diagnosis of lung adenocarcinoma