COL23A1 promotes tumor progression and glycolytic reprogramming in endometrial cancer via METTL14-m6A-YTHDF1 axis

Endometrial cancer (EC) is one of the most common gynecological malignancies, and its progression is tightly linked to extracellular matrix (ECM) remodeling and metabolic reprogramming. Collagen type XXIII alpha 1 (COL23A1), a transmembrane collagen, has been implicated in several cancers, but its expression pattern, functional role and upstream regulation in EC remain unclear. Public datasets (TCGA, GTEx, cBioPortal) were analyzed to characterize COL23A1 expression, clinicopathological correlations and prognostic value. The biological functions of COL23A1 in EC cells were assessed by qRT-PCR, Western blotting, CCK-8, colony formation, flow cytometry, Transwell assays and Seahorse extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) measurements. Untargeted metabolomics and RNA immunoprecipitation (RIP) were used to interrogate glycolytic metabolism and m⁶A modification. Xenograft models were established to validate the in vivo effects of COL23A1. COL23A1 was significantly upregulated in EC tissues and correlated with advanced clinicopathological features and poor overall survival. Genetic silencing of COL23A1 suppressed EC cell proliferation, clonogenicity, migration and invasion in vitro, and inhibited tumor growth in vivo. At the metabolic level, COL23A1 knockdown disrupted glycolytic metabolism, leading to reduced glucose uptake, lactate production, expression of key glycolytic enzymes and ECAR, accompanied by a compensatory increase in OCR. Integrative bioinformatic and experimental analyses showed that METTL14 installs m⁶A modifications on COL23A1 mRNA, whereas the m⁶A reader YTHDF1 binds and stabilizes the modified transcript, thereby sustaining COL23A1 expression. Rescue experiments demonstrated that COL23A1 is required for METTL14- and YTHDF1-driven glycolytic reprogramming and oncogenic phenotypes in EC cells. COL23A1 acts as a previously unrecognized oncogenic driver in endometrial cancer, promoting tumor progression and glycolysis-dependent metabolic reprogramming through a METTL14-m⁶A-YTHDF1-COL23A1 axis. Targeting this m⁶A-dependent pathway may offer a promising therapeutic strategy for endometrial cancer.

The online version contains supplementary material available at 10.1007/s10616-026-00898-9.