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This condition poses a formidable challenge in neurocritical care, with major subtypes encompassing sepsis\u2010associated encephalopathy, hepatic encephalopathy, hypoxic\u2013ischemic encephalopathy, diabetic encephalopathy, uremic encephalopathy, and toxic encephalopathy. The current therapeutic landscape reveals a critical deficiency in effective neuroprotective interventions, highlighting an urgent need for novel treatment strategies. Small\u2010molecule compounds, particularly those derived from natural products, offer a promising therapeutic paradigm due to their multitarget capabilities and potential for network\u2010level modulation of pathogenic processes. However, advancement in this field remains constrained by several fundamental limitations: fragmented mechanistic insights, ill\u2010defined target networks, and insufficient clinical translation. To address these challenges, this review systematically synthesizes contemporary evidence to delineate the etiopathogenesis of these encephalopathies, with particular emphasis on the molecular mechanisms and cellular targets of small molecule drugs (especially natural products). Through a critical assessment of current research limitations, this review aims to establish a robust framework and provide forward\u2010looking perspectives to guide the development of targeted neuroprotective strategies and their clinical translation.<\/jats:p>","DOI":"10.1002\/mco2.70802","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T07:21:27Z","timestamp":1780903287000},"source":"Crossref","is-referenced-by-count":0,"title":["Encephalopathy: Cause, Pathogenesis, and Treatment"],"prefix":"10.1002","volume":"7","author":[{"given":"Shimeng","family":"Lv","sequence":"first","affiliation":[{"name":"First Clinical Medical College Shandong University of Traditional Chinese Medicine  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Zhong","sequence":"additional","affiliation":[{"name":"Institute of Child and Adolescent Health School of Public Health Peking University  Beijing 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