{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T06:33:39Z","timestamp":1792996419203,"version":"4.5.0"},"reference-count":26,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:00:00Z","timestamp":1792022400000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical & Translational Med"],"published-print":{"date-parts":[[2026,10]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n Acquired resistance to sorafenib in hepatocellular carcinoma (HCC) is accompanied by coordinated changes in oxidative\u2010stress handling and regulated cell\u2010death pathways, yet how membrane organisation connects these adaptations is not fully resolved. We therefore examined whether B4GALNT1, a ganglioside biosynthetic glycosyltransferase, couples changes in ganglioside composition and lipid\u2010raft architecture to ferroptosis regulation and caspase\u20101\/GSDMD\u2010associated signalling in sorafenib\u2010resistant HCC.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We combined TCGA\u2010LIHC analysis, single\u2010cell transcriptomics, pathway\u2010level analyses, and graph attention network modelling with a treatment\u2010annotated local cohort of 92 patients with HCC who received sorafenib. Functional experiments were conducted in Huh7\/Huh7\u2010SR cells and additional liver\u2010tumour models using B4GALNT1 gain\u2010 and loss\u2010of\u2010function, an independent second\u2010sgRNA knockout clone, GM1 rescue, and re\u2010expression of either wild\u2010type B4GALNT1 or the catalytic\u2010loss D358A variant. Validation included ganglioside profiling, detergent\u2010resistant membrane isolation, lipid\u2010raft disruption\/repletion, ferroptosis\u2010directed pharmacology, cell\u2010death measurements, and xenograft studies.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n B4GALNT1 was enriched in tumour\u2010associated hepatocyte populations and was upregulated in Huh7\u2010SR cells. In the local cohort, higher B4GALNT1 protein abundance tracked with less favourable response to sorafenib and poorer survival outcomes. Increasing B4GALNT1 shifted ganglioside abundance toward GM2\/GM1\/GD2 and increased GM1\u2010enriched raft\u2010associated fractions, whereas knockout produced reciprocal changes. B4GALNT1\u2010high cells showed increased GPX4 and SLC7A11, reduced lipid peroxidation and labile Fe\n 2<\/jats:sup>\n +<\/jats:sup>\n , and lower ferroptotic injury. At the same time, caspase\u20101\/GSDMD\u2010associated signalling and IL\u20101\u03b2\/IL\u201018 release increased without widespread terminal membrane lysis. Exogenous GM1 partially rescued knockout\u2010associated changes, and wild\u2010type B4GALNT1 restored the phenotype more effectively than the D358A mutant. Concordant directional effects were observed in additional cell models and in xenografts.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n The data are consistent with a model in which B4GALNT1 reshapes ganglioside composition and GM1\u2010enriched membrane microdomains, thereby supporting a drug\u2010adapted state that combines greater ferroptosis resistance with restricted caspase\u20101\/GSDMD\u2010associated membrane permeabilisation. This integrated phenotype accompanies reduced sorafenib responsiveness and offers a mechanistic basis for acquired resistance in HCC.<\/jats:p>\n <\/jats:sec>\n \n HIGHLIGHTS<\/jats:title>\n \n \n \n B4GALNT1 is associated with sorafenib resistance and poorer outcomes in treated HCC.<\/jats:p>\n <\/jats:list-item>\n \n B4GALNT1 remodels gangliosides and lipid rafts, limiting ferroptotic injury.<\/jats:p>\n <\/jats:list-item>\n \n Caspase\u20101\/GSDMD signalling increases without widespread terminal membrane lysis.<\/jats:p>\n <\/jats:list-item>\n \n Genetic rescue and cross\u2010model studies support B4GALNT1 specificity.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/ctm2.70873","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T09:52:17Z","timestamp":1792057937000},"source":"Crossref","is-referenced-by-count":0,"title":["Graph attention network\u2010driven single\u2010cell omics analysis reveals how B4GALNT1\u2010mediated glycosylation remodelling of the ferroptosis\u2013pyroptosis network promotes drug resistance in hepatocellular carcinoma"],"prefix":"10.1002","volume":"16","author":[{"given":"Lihan","family":"Bie","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine The Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biao","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine The Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitao","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine The Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuwen","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine The Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyang","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine The Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhouhong","family":"Xiang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine The Seventh People's Hospital Affiliated to Shanghai University of Traditional Chinese Medicine Shanghai 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