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This study explores the effect of AFP regulating GMR (Glucose metabolic reprogramming) on the tolerance of HCC cells to sorafenib. Thirty clinical liver cancer samples and multi\u2010omics databases were collected; the expression of AFP, GMR\u2010related proteins, pyruvate kinase M2 (PKM2), and the PI3K\/AKT signalling pathway\u2010associated proteins were assessed using immunohistochemistry (IHC) or Western blotting. MTT, cloning assays, flow cytometry, and TUNEL were performed to evaluate the effects of AFP on HCC resistance to sorafenib. Alterations in glucose consumption, lactate dehydrogenase activity, and ATP production were measured. Co\u2010immunoprecipitation and immunofluorescence experiments were conducted to determine how AFP interacts with PKM2. An in\u00a0vivo mouse tumour model was used to investigate the restoration of tumorigenesis and development. The results indicated that AFP inhibited sorafenib\u2010induced apoptosis of HCC cells. AFP activated the PI3K\/AKT signalling pathway to promote the GMR\u2010related protein expression and enzyme activity. Particularly, AFP's interaction with PKM2 stimulated the activity of PKM2 to enhance GMR, contributing to HCC resistance to sorafenib. In\u00a0vivo experiments demonstrated that inhibition of AFP expression attenuated tumorigenesis and growth, and this effect was restored by overexpression of PKM2; PKM2 played a critical activated role in AFP mediating the GMR in HCC. In conclusion, AFP activates the PI3K\/AKT signalling pathway to augment aerobic glycolysis in HCC cells, leading to HCC resistance to sorafenib. Inhibition of AFP expression and targeting of PKM2 may represent a novel approach for clinically reversing sorafenib tolerance in HCC patients.<\/jats:p>","DOI":"10.1111\/jcmm.71226","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T04:10:27Z","timestamp":1780632627000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>AFP<\/scp>\n                    Stimulates Glucose Metabolic Reprogramming Contributing to Hepatocellular Carcinoma Resist Sorafenib Through Activating\n                    <scp>PI3K<\/scp>\n                    \/\n                    <scp>AKT<\/scp>\n                    Signalling Pathway"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-1815-826X","authenticated-orcid":false,"given":"Yuli","family":"Zhou","sequence":"first","affiliation":[{"name":"Key Laboratory of Tropical Translational Medicine, Ministry of Education, and Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, School of Basic Medical Sciences Hainan Medical University  Haikou Hainan Province P.R. 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