ATP5PB suppresses colorectal cancer progression by restraining the Galectin-3/PI3K/AKT signaling axis

Background Colorectal cancer is one of the most common malignancies worldwide, and uncontrolled proliferation, local invasion, and distant metastasis remain the principal causes of poor clinical outcomes. ATP synthase F1 subunit beta, encoded by ATP5PB, is a key component of mitochondrial ATP synthase involved in oxidative phosphorylation and cellular energy metabolism. However, the biological function and molecular mechanism of ATP5PB in colorectal cancer progression remain unclear. Methods We used public single-cell transcriptomic data and a clinical cohort of 87 colorectal cancer patients to analyze ATP5PB expression patterns and clinical relevance in CRC. ATP5PB expression was evaluated in CRC tissues, adjacent nontumor tissues, and CRC cell lines by immunohistochemistry, reverse transcription quantitative polymerase chain reaction, and western blotting. The association between ATP5PB expression and clinicopathological characteristics or patient prognosis was analyzed using clinical information and Kaplan–Meier survival analysis. The role of ATP5PB in CRC cells was determined by gain- and loss-of-function experiments in LOVO cells, including Cell Counting Kit-8 and Transwell migration and invasion assays. Molecular docking, co-immunoprecipitation, and immunofluorescence staining were performed to investigate the interaction between ATP5PB and Galectin-3. Western blotting was used to examine the activation of the PI3K/AKT pathway and downstream metastasis-related molecules. Subcutaneous xenograft models were established to investigate the effects of ATP5PB on tumor growth and to validate the ATP5PB/Galectin-3/PI3K/AKT signaling axis in vivo. Results We found that ATP5PB was downregulated in CRC cells, tissues, and cell lines. Low ATP5PB expression was associated with advanced tumor stage, lymph node metastasis, and poor overall survival. ATP5PB overexpression inhibited CRC cell proliferation, migration, and invasion, whereas ATP5PB knockdown produced the opposite effects. Mechanistically, ATP5PB interacted with Galectin-3 and suppressed activation of the PI3K/AKT pathway. In vivo, ATP5PB overexpression reduced xenograft tumor growth, while ATP5PB knockdown promoted tumor growth and activated Galectin-3/PI3K/AKT signaling. Conclusion ATP5PB may serve as a potential prognostic biomarker, and restoration of ATP5PB activity or targeting the Galectin-3/PI3K/AKT axis may represent a therapeutic strategy for CRC.