Dandan Zhou,1 Mengzhuo Zheng,2 Di Cui,3 Bo Guan,4 Chun Luo5 1Urology Surgery, Fuyang Normal University Affiliated First Hospital, Fuyang, Anhui, People’s Republic of China; 2College of Informatics, Huazhong Agricultural University, Wuhan, Hubei, People’s Republic of China; 3Fuyang Medical College, Fuyang Normal University, Fuyang, Anhui, People’s Republic of China; 4Urology Surgery, Fuyang City People’s Hospital, Fuyang, Anhui, People’s Republic of China; 5Pediatric surgery, Fuyang Normal University Affiliated First Hospital, Fuyang, Anhui, People’s Republic of ChinaCorrespondence: Chun Luo, Email 18155855080@163.comBackground: Clear cell renal cell carcinoma is driven by hypoxia adaptation and pathological angiogenesis mediated by VHL inactivation and HIF signaling. Current treatments including VEGF-targeted therapy and immune checkpoint blockade often face resistance or inadequate response, highlighting the need for new biomarkers linked to tumor metabolism and therapy sensitivity.Methods: A comprehensive machine learning approach was combined with Weighted Gene Co-Expression Network Analysis of TCGA and single-cell datasets to identify hypoxia- and angiogenesis-related prognostic genes. Among them, AK3 was selected for functional validation in ccRCC tissues and cell lines, with mechanistic studies performed in vitro and in vivo.Results: AK3 was significantly downregulated in ccRCC and associated with poor prognosis. AK3 overexpression inhibited tumor cell proliferation and migration by suppressing PI3K/AKT/GSK3β signaling and reduced tumor progression in nude mice. Furthermore, AK3 enhanced oxaliplatin sensitivity by increasing reactive oxygen species and reducing lipid droplet accumulation, implicating its role in metabolic and redox regulation.Conclusion: AK3 functions as a hypoxia-angiogenesis-related tumor suppressor in ccRCC, linking energy metabolism to therapeutic response. AK3 expression may serve as a prognostic biomarker and a predictor of chemotherapy sensitivity, providing a basis for future stratified treatment or combination therapy strategies in ccRCC.Keywords: hypoxia, AK3, resistance, clear cell renal carcinoma
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