PYCR1 induces ferroptosis via the PI3K/Akt signaling pathway to regulate the proliferation and migration of osteosarcoma.

Osteosarcoma treatment outcomes are compromised by increased drug resistance, distant metastasis, and tumor recurrence. While Pyrrolidine-5-carboxylic acid reductase 1(PYCR1) knockdown has been shown to inhibit tumor proliferation and migration in certain cancers. Its effects in osteosarcoma and regulatory mechanisms within osteosarcoma cells have not been explored. This study investigated the role of PYCR1 in osteosarcoma proliferation and its potential molecular mechanisms. The expression of PYCR1 was assessed in osteosarcoma tissues by immunohistochemistry and its correlation with clinical outcomes was determined. Subsequently, lentivirus-mediated knockdown and over expression of PYCR1 was achieved in osteosarcoma cells to evaluate its impact on proliferation, colony formation, and migration ability. The PI3K/Akt signaling pathway and its downstream effector COL1A1 were investigated using a combination of biomarker analysis, transcriptome sequencing, and co-immunoprecipitation assays. Subsequent silencing of COL1A1 induced phenotypic changes and confirmed tumorigenicity in vivo. The ferroptosis agonist Erastin and its specific antagonist Ferrostatin-1 (Fer-1) were combined with PYCR1 knockdown to explore their correlation with ferroptosis. By applying the pathway inhibitor LY294002, it was confirmed that the PI3K/Akt pathway is crucial for osteosarcoma proliferation. This study confirms that PYCR1 drives osteosarcoma cell proliferation and migration through three key mechanisms: regulating downstream genes, inhibiting ferroptosis, and activating the PI3K/Akt signaling pathway.