{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T05:13:42Z","timestamp":1783660422782,"version":"3.55.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Mushroom poisoning caused by\n                      <jats:italic>Amanita phalloides<\/jats:italic>\n                      , primarily mediated by the toxin \u03b1-amanitin (AMA), frequently leads to fatal liver failure, yet no specific antidote is currently available. Although AMA is known to inhibit RNA polymerase II, its complete cytotoxic mechanism remains unclear. This study aimed to repurpose the antifungal drug posaconazole as a first-in-class antidote targeting the host glycosylation machinery to mitigate AMA-induced liver injury.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Posaconazole was identified through STT3B-focused virtual screening followed by\n                      <jats:italic>in vitro<\/jats:italic>\n                      cell-based screening. Its protective effects were evaluated in 2D and 3D cell cultures via microscopy, cell viability assays and Calcein-AM\/PI staining. Therapeutic efficacy\n                      <jats:italic>in vivo<\/jats:italic>\n                      was assessed in a lethal mouse model by serum biochemical analysis, H&amp;amp;E, immunohistochemistry, and survival analysis. The interactions between posaconazole and STT3B was examined by molecular docking and an endoplasmic reticulum-localized luciferase reporter assay. N-glycosylation level was analyzed by lectin staining. ST6GAL1 was knockdown by shRNA. The concentrations of AMA were quantified by high-performance liquid chromatography.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Posaconazole robustly protected human hepatocytes from AMA-induced toxicity in both 2D and 3D cultures. In a lethal mouse model, post-exposure treatment with posaconazole significantly attenuated AMA-induced liver injury and improves survival, achieving efficacy comparable to prior candidate. Mechanistically, posaconazole potentially inhibited the STT3B-mediated N-glycosylation, thereby suppressing down-stream sialylation. The genetic ablation of sialyltransferase ST6GAL1 confirmed that reduced sialylation limits cellular AMA uptake and confers resistance to toxicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our work unveils a critical glycosylation-dependent pathway for AMA toxicity and nominates posaconazole as a clinically translatable, host-directed therapeutic candidate for the treatment of lethal Amanita phalloides poisoning.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1864484","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T04:24:47Z","timestamp":1783657487000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Posaconazole mitigates \u03b1-amanitin-induced liver injury by inhibiting STT3B-mediated glycosylation and cellular uptake"],"prefix":"10.3389","volume":"17","author":[{"given":"Bei","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Sun Yat-Sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenwei","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center","place":["Guangzhou, China"]},{"name":"Department of Liver Surgery, Sun Yat-sen University Cancer Center","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizhi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Sun Yat-Sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjie","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Sun Yat-Sen University","place":["Guangzhou, China"]},{"name":"School of Pharmaceutical Sciences, Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahao","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Sun Yat-Sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Sun Yat-Sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Sun Yat-Sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubo","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Sun Yat-Sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiao-Ping","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolism and Aging, School of Pharmaceutical Sciences, Shenzhen Campus of Sun Yat-sen University","place":["Shenzhen, China"]},{"name":"Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University","place":["Guangzhou, China"]},{"name":"State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University Shenzhen Campus","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke-Jing","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The First Affiliated Hospital of Sun Yat-Sen University","place":["Guangzhou, China"]},{"name":"Division of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1585","DOI":"10.1016\/j.cmi.2024.07.019","article-title":"Posaconazole gastro-resistant tablets for preventing invasive fungal disease after haematopoietic stem cell transplantation: a propensity-matched cohort study","volume":"30","author":"Cao","year":"2024","journal-title":"Clin. 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