The CLIC1-PKM2 axis orchestrates glycolytic metabolism to accelerate gastric cancer progression.

[BACKGROUND] Metabolic reprogramming is a hallmark of malignant transformation and supports tumor proliferation and survival. Chloride intracellular channel protein 1 (CLIC1) has been implicated in multiple oncogenic processes; however, its mechanistic role in regulating glycolysis in gastric cancer (GC) remains largely unknown. This study aimed to elucidate how CLIC1 modulates PKM2-dependent glycolytic metabolism and its impact on gastric tumor progression.

[METHODS] Bioinformatic analyses were performed using TCGA and GEO datasets to assess correlations between CLIC1 and glycolytic pathways. Immunohistochemistry was used to assess CLIC1 and PKM2 expression and their correlation in GC. Functional assays, including Seahorse extracellular flux analysis, glucose/lactate quantification, and ATP measurement were used to evaluate glycolytic activity. Protein interactions were analyzed by co-immunoprecipitation, GST pull-down, and mass spectrometry. Cellular proliferation, migration, and invasion were assessed by CCK-8, wound healing, and Transwell assays. Xenograft mouse models were established to evaluate in vivo tumorigenic capacity and the therapeutic effects of glycolytic inhibition.

[RESULTS] CLIC1 expression was positively correlated with glycolytic pathway activity in GC. CLIC1 and PKM2 were highly expressed in gastric cancer tissues and showed a positive correlation. CLIC1 knockdown suppressed glycolysis and inhibited GC cell proliferation, migration, and invasion, whereas CLIC1 overexpression exerted the opposite effects. Mechanistically, CLIC1 directly interacted with the C-terminal domain of PKM2, stabilizing its dimeric form, thereby facilitating glycolytic flux and nuclear PKM2 accumulation. Pharmacological inhibition of PKM2 or glycolysis attenuated CLIC1-induced tumor growth both in vitro and in vivo.

[CONCLUSIONS] This study identifies CLIC1 as a novel metabolic regulator that drives glycolytic reprogramming through direct interaction with PKM2 in gastric cancer. Targeting the CLIC1-PKM2 axis may provide a promising therapeutic strategy for metabolic intervention in GC and highlights a potential translational target for future clinical application.