SLC28A1 inhibits clear cell renal cell carcinoma progression by affecting arachidonic acid metabolism: A novel nucleoside transporter-based targeted therapy strategy.

Clear cell renal cell carcinoma (ccRCC) is a significant clinical challenge due to its heterogeneous nature and variable prognosis. This study aimed to evaluate the prognostic role of nucleoside transporters (NTs) in ccRCC, elucidate the mechanisms underlying the key NT in tumor progression, and develop a targeted therapeutic strategy. Utilizing the Cancer Genome Atlas (TCGA) database, Lasso regression analysis was used for identifying NTs that significantly influenced ccRCC prognosis, which were subsequently used for constructing a risk scoring model. Furthermore, other clinicopathological risk factors were combined to construct a prognostic nomogram incorporating the risk scoring model. Univariate and multivariate Cox regression analyses revealed SLC28A1 as a key NT, and its expression was validated through bioinformatics tools, single-cell sequencing, and cellular/tissue assays. Functional assessments via knockdown and overexpression experiments indicated the role of SLC28A1 in inhibiting proliferation, migration, and invasion of ccRCC cells. In addition, its expression was affected by reactive oxygen species (ROS) and involved in arachidonic acid (AA) metabolism through regulating PLA2G12A via the MAPK signaling pathway, to promote ferroptosis. Moreover, sensitive small molecule drugs binding to SLC28A1 were screened using the Cmap database, which identified sapitinib with therapeutic potential. The efficacy of sapitinib was further enhanced through targeted nanoparticle delivery, significantly inhibiting tumor growth in both in vitro and in vivo models while ensuring biosafety. In conclusion, this research elucidates the mechanism by which SLC28A1 exerts its inhibitory effect in ccRCC and proposes a promising targeted nanotherapeutic approach, offering new insights and strategies for the management of ccRCC.