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Background  Recurrence is a major challenge in early‐stage lung adenocarcinoma (LUAD) treatment. Here, we investigated the role and mechanism of high‐mobility group AT‐hook 1 (HMGA1) and glucose‐regulated protein 75‐kDa (GRP75) in stage I LUAD and evaluated their potential as biomarkers for predicting the recurrence and prognosis of stage I LUAD.    Methods  The TCGA dataset was used to investigate the clinical significance of HMGA1 and GRP75 in early‐stage LUAD. The biological functions of HMGA1 and GRP75 in LUAD were investigated both in vitro and in vivo through overexpression and knockdown experiments. The interaction and regulation between HMGA1 and GRP75 were evaluated with coimmunoprecipitation and ubiquitination assays. The downstream signaling pathway of the GRP75/HMGA1 axis was investigated by mRNA‐sequencing analysis.    Results  Both HMGA1 expression levels and GRP75 expression levels were associated with recurrence in stage I LUAD patients. In particular, HMGA1 had potential as an independent prognostic factor in stage I LUAD patients. Overexpression of GRP75 or HMGA1 significantly stimulated LUAD cell growth and metastasis, while silencing GRP75 or HMGA1 inhibited LUAD cell growth and metastasis in vitro and in vivo. Importantly, GRP75 inhibited ubiquitination‐mediated HMGA1 degradation by directly binding to HMGA1, thereby causes HMGA1 upregulation in LUAD. In addition, the GRP75/HMGA1 axis played its role by activating JNK/c‐JUN signaling in LUAD.    Conclusions  The activation of GRP75/HMGA1/JNK/c‐JUN signaling is an important mechanism that promotes the progression of stage I LUAD, and a high level of HMGA1 is a novel biomarker for predicting recurrence and a poor prognosis in stage I LUAD patients.

GRP75 ‐mediated upregulation of HMGA1 stimulates stage I lung adenocarcinoma progression by activating JNK / c‐JUN signaling