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Here, we uncovered the natural compound neferine (Nef) as a pharmacological modulator of BAP31 that suppressed microglial activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      Using thermal protein profiling (TPP), we identified BAP31 as the primary target of Nef. Biochemical and structural analyses were employed to characterise Nef\u2010BAP31 interactions. We evaluated ER stress and mitochondrial energy metabolism homeostasis using techniques such as STER super\u2010resolution technology, flow cytometry, western blot,\n                      <jats:italic>etc<\/jats:italic>\n                      . In vivo validation utilised two models: lipopolysaccharide (LPS)\u2010induced endotoxaemia and middle cerebral artery occlusion (MCAO) for ischaemic stroke, combining behavioural tests, cytokine profiling and histopathological assessments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>Nef functioned as a \u2018molecular glue\u2019 by binding to BAP31's coiled\u2010coil CC2 domain to induce stable dimerisation. We revealed that dimerised BAP31 triggered ER membrane remodelling, which disrupted ER\u2013mitochondria contact sites and preserved mitochondrial energy metabolism homeostasis, thereby blocking inflammatory cytokine release. In vivo, Nef attenuated neuroinflammation in endotoxaemia mice and further conferred neuroprotection against ischaemic stroke in a MCAO model by inhibiting microglia\u2010driven neuronal injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>In summary, our work reveals that BAP31 is a master regulator of ER\u2010mitochondria communication during microglial activation and introduces a paradigm\u2010shifting \u2018molecular glue\u2019 strategy for targeting ER\u2010resident proteins. Additionally, these findings redefine the pharmacological landscape for modulating organelle interactions in microglia involved in neuroinflammatory diseases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70277","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T00:15:05Z","timestamp":1764720905000},"page":"1878-1900","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Molecular glue neferine induces BAP31 homodimerisation to disrupt endoplasmic reticulum\u2013mitochondria crosstalk for anti\u2010neuroinflammation in ischaemic stroke"],"prefix":"10.1111","volume":"183","author":[{"given":"Ya\u2010Xuan","family":"Zhu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences Peking University  Beijing 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