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Ganoderic acids (GAs), the primary bioactive compounds isolated from\n                    <jats:italic>Ganoderma lucidum<\/jats:italic>\n                    , exhibit well\u2010demonstrated anti\u2010inflammatory properties. This study aimed to investigate the neuroprotective potential of GAs in the context of ischemic stroke. Mice subjected to transient middle cerebral artery occlusion (tMCAO) served as an in vivo model of focal cerebral ischemia, while LPS\u2010treated microglial cells were utilized as an in vitro model to evaluate microglial activation. GAs treatment significantly alleviated cerebral ischemic injury, inhibited microglial overactivation, and decreased inflammatory cytokine expression in both in vitro and in vivo models. Mechanistically, eight principal monomers in GAs, particularly GA\u2010K, were found to target myeloid differentiation protein 2 (MD2), thereby preventing its interaction with Toll\u2010like receptor 4 (TLR4), and subsequently inhibiting MAPK and NF\u2010\u03baB pathways. MD2 was found to be overexpressed\u00a0under ischemic conditions. In MD2\u2010deficient mice, microglial activation was inhibited, and neuroprotection against ischemic injury was observed, unaffected by GAs. These findings suggest that GAs, particularly GA\u2010K, provide neuroprotection in ischemic stroke by modulating microglia\u2010mediated neuroinflammation through MD2, which may serve as a promising therapeutic target for stroke patients.\n                  <\/jats:p>","DOI":"10.1002\/exp.20240147","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T06:21:21Z","timestamp":1771482081000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Ganoderic Acids Alleviate Neuroinflammation by Targeting Myeloid Differentiation Factor 2 for Ischemic Stroke Therapy"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9988-8670","authenticated-orcid":false,"given":"Ang","family":"Ma","sequence":"first","affiliation":[{"name":"State Key Laboratory of Vascular Homeostasis and Remodeling Department of Pharmacology School of Basic Medical Sciences Peking University  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