KDELR2 promotes the progression of non-small cell lung cancer by regulating HIF-1α mediated glycolysis

Introduction Across the world, lung cancer remains the foremost cause of death attributed to cancer, contributing to nearly one in five of cancer deaths. As the main histological form, non-small cell lung cancer (NSCLC) constitutes roughly 80%–85% of total diagnosed lung cancer cases. Patients diagnosed with advanced NSCLC have a 5-year survival rate lower than 20%, and persistent problem of drug resistance underscores the importance of developing new safe and efficacious drugs and exploring innovative therapeutic targets. The Lys-Asp-Glu-Leu (KDEL) endoplasmic reticulum (ER) protein retention receptors (KDELRs) is one of the earliest discovered intracellular transport receptors and essential for preserving the integrity of the early secretory pathway. Evidence indicates that KDELR2 facilitates the invasion and migration of NSCLC, although the fundamental mechanisms behind this remain poorly understood. The research suggestes that KDELR2 could enhance abilities of proliferation, migration, and invasion of NSCLC through hypoxia-inducible factor 1α (HIF-1α) dependent glycolytic metabolism and identified KDELR2 as a potential molecular target for the novel drug pseudoginsenoside Rh2 (P-G-Rh2), thereby offering a new therapeutic target and a potentially effective treatment agent for NSCLC. Methods The levels of KDELR2 were measured through real-time fluorescence quantitative PCR (RT‐qPCR), western blot, and immunohistochemistry (IHC). In vitro assays were carried out to evaluate impact of KDELR2 on functions of NSCLC cells and explore the underlying mechanism through cell counting kit‐8 (CCK‐8), western blot, transwell assays, and wound healing. Additionally, nude mice xenograft models were conducted for validating role of P‐G‐Rh2 in suppressing progression of NSCLC. Results KDELR2 expression is upregulated in NSCLC tissues, and its increased levels enhance the proliferation, invasion, and metastasis of NSCLC. Mechanistic studies indicate that KDELR2 drives progression of NSCLC by elevating HIF‐1α and subsequently activating glycolysis. Additionally, KDELR2 is recognized as a potential molecular target of P‐G‐Rh2. Further investigation reveals that P‐G‐Rh2 suppresses progression of NSCLC through by regulating the KDELR2/HIF‐1α/glycolysis axis. Conclusion KDELR2 promotes the progression of NSCLC via HIF‐1α-mediated glycolysis. Therefore, targeting the KDELR2/HIF-1α/glycolysis signaling pathway may become an effective therapeutic strategy for NSCLC. Meanwhile, KDELR2 is a potential molecular target of P‐G‐Rh2, indicating that P‐G‐Rh2 represents a promising novel therapeutic approach for NSCLC.