Enzymatically inactive chitinase-like protein CHI3L1 drives inflammatory response and promotes tumor progression. However, its role in gastric cancer (GC) tumorigenesis and metastasis has not yet been fully elucidated. We determined the significance of CHI3L1 expression in patients with GC. We also explored an as-yet unknown receptor of CHI3L1 and investigated the involved signaling in GC metastasis. CHI3L1 expression was evaluated by immunoblotting, tissue microarray-based immunohistochemistry analysis (n = 100), and enzyme linked immunosorbent assay (ELISA) (n = 150). The interactions between CD44 and CHI3L1 or Interleukin-13 receptor alpha 2 (IL-13Rα2) were analyzed by co-immunoprecipitation, immunofluorescence co-localization assay, ELISA, and bio-layer interferometry. The roles of CHI3L1/CD44 axis in GC metastasis were investigated in GC cell lines and experimental animal model by gain and loss of function. CHI3L1 upregulation occurred during GC development, and positively correlated with GC invasion depth, lymph node status, and tumor staging. Mechanically, CHI3L1 binding to CD44 activated Erk and Akt, along with β-catenin signaling by phosphorylating β-catenin at Ser552 and Ser675. CD44 also interacted with IL-13Rα2 to form a complex. Notably, CD44v3 peptide and protein, but not CD44v6 peptide or CD44s protein, bound to both CHI3L1 and IL-13Rα2. Our in vivo and in vitro data further demonstrated that CHI3L1 promoted GC cell proliferation, migration, and metastasis. CHI3L1 binding to CD44v3 activates Erk, Akt, and β-catenin signaling, therefore enhances GC metastasis. CHI3L1 expression is a novel biomarker for the prognosis of GC, and these findings have thus identified CHI3L1/CD44 axis as a vital pathway and potential therapeutic target in GC.

Background: Gastric cancer (GC) metastasis remains a leading cause of treatment failure and mortality. While long non-coding RNAs (lncRNAs) are implicated in metastasis, their mechanisms remain unclear. Methods: We performed transcriptome sequencing on 61 GC patients stratified by metastatic potential, identifying CASC19 as a metastasis-associated lncRNA. Its functional role was validated in vitro and in vivo. Mechanistic studies included RNA immunoprecipitation, mRNA stability assays, and ferroptosis analysis. Results: CASC19 promoted GC metastasis by forming a complex with DHX9 to stabilize c-Myc mRNA via its CRD domain, driving oncogenic and PD-L1-mediated immune evasion. Additionally, the CASC19/DHX9 complex upregulated GPX4 by enhancing mRNA stability, inhibiting ferroptosis to facilitate metastasis. Conclusions: The CASC19/DHX9/c-Myc-PD-L1 and CASC19/DHX9/GPX4 axes represent promising therapeutic targets for metastatic GC.