Objective To explore the mechanism that regulated FASN during distant metastasis of osteosarcoma.Meth-ods Based on the anoikis resistance model of osteosarcoma,online prediction,proteomic sequencing,and CO-IP experiments were used to screened the E3 ligase interacting with FASN;Western blot and ubiquitination experiments were used to detect the ubiquitination level of FASN proteins;and we applied flow cytometry,tumor spheroid formation experiments,and the in situ osteo-sarcoma lung metastasis model of nude mice to explore the regulation mechanism of FASN ubiquitination in the distant metastasis of osteosarcoma.ubiquitination in distant metastasis of osteosarcoma.Results The ubiquitination level of FASN was decreased while its expression was increased in loss-of-nest apoptosis-resistant cells,and the predicted results suggested that SYVN1 was an E3 ligase for FASN ubiquitination;overexpression of SYVN1 induced loss-of-nest apoptosis of osteosarcoma cells and decreased the ability of osteosarcoma to form tumors and metastasize remotely in situ.Conclusion The E3 ligase SYVN1 was reduced in the process of resistance to loss-of-nest apoptosis in osteosarcoma,resulting in decreased ubiquitination and increased expression of FASN,and overexpression of SYVN1 inhibited osteosarcoma progression.