{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:51:32Z","timestamp":1791161492966,"version":"4.1.0"},"reference-count":66,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Academia Sinica and Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["AS-BRPT-112-09"],"award-info":[{"award-number":["AS-BRPT-112-09"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Galectin-3 (Gal3) acts as an intracellular sensor of lysosomal damage and a key driver of microglial activation and neuroinflammation in multiple neurodegenerative disorders. Despite its biological importance, no inhibitors have been identified that both modulate intracellular Gal3 activity and effectively cross the blood\u2013brain barrier. Here, we established an innovative high-content imaging platform using microglia expressing Gal3-GFP, allowing direct visualization of Gal3 puncta formation upon lysosomal damage as a phenotypic readout for compound screening.<\/jats:p>\n                  <jats:p>Through screening of \u223c24 000 small molecules, we identified berbamine hydrochloride as a potent inhibitor of Gal3 puncta formation with confirmed blood\u2013brain barrier permeability. Mechanistically, berbamine hydrochloride disrupts Gal3 oligomerization and Gal3\u2013TREM2 interaction via a unique allosteric mechanism distinct from the canonical glycan-binding domain. It attenuated lipopolysaccharide-induced inflammation in vitro and achieved sustained brain exposure in vivo.<\/jats:p>\n                  <jats:p>In the R6\/2 mouse model of Huntington\u2019s disease, berbamine hydrochloride effectively improved motor functions, reduced mutant huntingtin protein aggregation and restored crucial dopaminergic and ciliary signalling pathways. Transcriptomic profiling further identified Gal3 as a central regulatory hub within Huntington\u2019s disease-associated networks that were corrected upon treatment. Computational docking and molecular dynamics simulations further supported an allosteric binding mode distinct from the canonical glycan-binding domain of Gal3.<\/jats:p>\n                  <jats:p>Together, these findings establish berbamine hydrochloride as the first blood\u2013brain barrier-penetrant small molecule inhibitor targeting intracellular Gal3 with therapeutic benefit in Huntington\u2019s disease. Furthermore, the puncta-based screening strategy that we developed provides a robust platform for discovering intracellular modulators of Gal3 relevant to a wide range of neurological diseases.<\/jats:p>","DOI":"10.1093\/brain\/awag069","type":"journal-article","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T12:36:13Z","timestamp":1772195773000},"page":"3414-3430","source":"Crossref","is-referenced-by-count":2,"title":["Berbamine hydrochloride as a brain-penetrant galectin-3 inhibitor in a model of Huntington\u2019s disease"],"prefix":"10.1093","volume":"149","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7028-3873","authenticated-orcid":false,"given":"Jian Jing","family":"Siew","sequence":"first","affiliation":[{"name":"Institute of Biomedical Sciences, Academia Sinica , Taipei 115 ,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Wei","family":"Lee","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Academia Sinica , Taipei 115 ,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Mei","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Academia Sinica , Taipei 115 ,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsien-Ya","family":"Lin","sequence":"additional","affiliation":[{"name":"Institute of Biological Chemistry, Academia Sinica , Taipei 115 ,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ling","family":"Liu","sequence":"additional","affiliation":[{"name":"Genomics Research Center, Academia Sinica , Taipei 115 ,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Hsuan","family":"Lee","sequence":"additional","affiliation":[{"name":"Department and Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung University , Taipei 112 ,","place":["Taiwan"]},{"name":"Brain Research Center, National Yang Ming Chiao Tung University , Taipei 112 ,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Ta","family":"Wu","sequence":"additional","affiliation":[{"name":"Genomics Research Center, Academia Sinica , Taipei 115 ,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hung-Lin","family":"Chen","sequence":"additional","affiliation":[{"name":"Master Program in Clinical Genomics and Proteomics, Taipei Medical University , Taipei 110 ,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fu-Tong","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Academia Sinica , Taipei 115 ,","place":["Taiwan"]},{"name":"Department of Dermatology, Keck School of Medicine, University of Southern California , Los Angeles, CA 90033 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Hung","family":"Lin","sequence":"additional","affiliation":[{"name":"Institute of Biological Chemistry, Academia Sinica , Taipei 115 ,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5842-5429","authenticated-orcid":false,"given":"Yijuang","family":"Chern","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Academia Sinica , Taipei 115 ,","place":["Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,3,3]]},"reference":[{"key":"2026100419580676600_awag069-B1","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/s41577-022-00829-7","article-title":"The role of galectins in immunity and infection","volume":"23","author":"Liu","year":"2023","journal-title":"Nat Rev 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Neuropathol"},{"key":"2026100419580676600_awag069-B5","doi-asserted-by":"crossref","first-page":"9041","DOI":"10.18632\/aging.205014","article-title":"Galectin-3 promotes brain injury by modulating the phenotype of microglia via binding TLR-4 after intracerebral hemorrhage","volume":"15","author":"Liang","year":"2023","journal-title":"Aging (Albany NY)"},{"key":"2026100419580676600_awag069-B6","doi-asserted-by":"crossref","first-page":"4725","DOI":"10.1523\/JNEUROSCI.2312-22.2023","article-title":"Elevated galectin-3 is associated with aging, multiple sclerosis, and oxidized phosphatidylcholine-induced neurodegeneration","volume":"43","author":"Xue","year":"2023","journal-title":"J Neurosci"},{"key":"2026100419580676600_awag069-B7","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/s41582-020-0389-4","article-title":"Huntington disease: New insights into molecular pathogenesis and therapeutic 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