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The molecular chaperone Glucose\u2010Regulated Protein 78 (GRP78) is substantially elevated in NSCLC compared to normal tissues and cell lines. In clinical samples, GRP78 protein levels correlated with advanced tumor stage and lymph node metastasis. Pharmacological inhibition of GRP78 using BAPTA\u2010AM and GRP78\u2010IN\u20103 significantly suppressed NSCLC cell viability while promoting apoptosis. The inhibitors effectively attenuated cell migration by downregulating matrix metalloproteinases and reversed epithelial\u2010mesenchymal transition by modulating key cadherin expression profiles. Importantly, GRP78 inhibition substantially reduced cancer stem cell markers and impaired spheroid formation capability. Genetic knockdown of GRP78 in A549 and H1975 cells recapitulated the effects of pharmacological inhibition, reducing cell migration, reversing EMT, attenuating stemness, and suppressing \u03b2\u2010catenin signaling. Conversely, GRP78 overexpression in A549 and H1975 cells induced opposite effects, promoting mesenchymal markers, enhancing stemness proteins, and increasing spheroid size. Mechanistic studies revealed that this anti\u2010tumor activity operates through suppression of \u03b2\u2010catenin signaling mediated by SIX1, as evidenced by SIX1\u2010overexpression rescue experiments. These findings demonstrate that GRP78 acts as a key regulator of NSCLC stemness and metastatic potential by coordinating epithelial plasticity and stemness pathways, positioning it as a promising therapeutic target for NSCLC treatment.<\/jats:p>","DOI":"10.1002\/ddr.70359","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T18:23:19Z","timestamp":1785781399000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["GRP78 Drives NSCLC Stemness and EMT via a SIX1\/\u03b2\u2010Catenin Signaling Axis"],"prefix":"10.1002","volume":"87","author":[{"given":"Guoping","family":"Tong","sequence":"first","affiliation":[{"name":"Department of Respiratory and Tumor Internal Medicine, Chinese Academy of Medical Sciences Cancer Hospital Shanxi Hospital Shanxi Cancer Hospital Taiyuan City Shanxi Province 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