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Dysregulation of Shh signalling has been implicated in degenerative diseases yet therapeutic interventions targeting this pathway remain limited. PUR demonstrates broad therapeutic efficacy across diverse preclinical disease models by activating both canonical GLI\u2010mediated transcription and non\u2010canonical Shh pathways, resulting in neuroprotection, reduced neuroinflammation, enhanced blood\u2013brain barrier integrity and tissue regeneration. In contrast to previous assumptions that Shh pathway activation requires endogenous ligand binding, PUR bypasses this requirement through direct Smoothened engagement, offering a pharmacologically tractable approach to pathway modulation. Preclinical studies demonstrate that PUR enhances motor neuron survival in amyotrophic lateral sclerosis models, protects dopaminergic neurons in Parkinson's disease, reverses behavioural abnormalities in autism spectrum disorder, promotes neurovascular repair following stroke, restores myelin integrity in multiple sclerosis models and drives osteogenic differentiation in bone tissue engineering applications. Beyond its established Smoothened agonist activity, recent evidence identifies PUR as a positive allosteric modulator of the secretin receptor, expanding its therapeutic scope to include cardiovascular applications such as hypertension management through enhanced nitric oxide bioavailability.<\/jats:p>","DOI":"10.1111\/jcmm.71349","type":"journal-article","created":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T04:47:20Z","timestamp":1788583640000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Therapeutic Potential of Purmorphamine Across Disease Models"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6997-1937","authenticated-orcid":false,"given":"Ashis","family":"Dhar","sequence":"first","affiliation":[{"name":"Department of Neurological Surgery University of Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7337-2892","authenticated-orcid":false,"given":"Ahnaf Dil","family":"Sharar","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery University of Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saikarthik","family":"Papisetty","sequence":"additional","affiliation":[{"name":"University of Minnesota Medical School  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0543-396X","authenticated-orcid":false,"given":"Mohammad","family":"Bydon","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery University of Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7878-316X","authenticated-orcid":false,"given":"F. 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