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Rats and mice are largely devoid of neuromelanin, although it is present in some other non-primate species. This pigment is notable for its age-related accumulation and has been linked to the pathophysiology of various neurodegenerative diseases, especially Parkinson's disease. Research has increasingly suggested that neuromelanin or its precursors trigger cellular stress, including neuroinflammation, apoptosis, oxidative stress, mitochondrial dysfunction, and impaired autophagy. Collectively, these mechanisms significantly contribute to neurodegeneration. Additionally, neuromelanin can interact with various neurotoxic molecules, potentially forming complexes that may provide protective benefits against neurotoxicity. However, extensive studies also suggest that this interaction can have a double-edged effect; while it may sequester harmful substances, it can simultaneously increase cellular stress and enhance neuronal toxicity, creating a detrimental cycle. We review the multifaceted roles of neuromelanin in the brain, discussing how its properties and interactions contribute to cellular stress and the progression of neurodegenerative processes. In the context of neurotoxic mechanisms, we also address potential therapeutic targets for Parkinson\u2019s disease.<\/jats:p>","DOI":"10.1007\/s10495-025-02156-3","type":"journal-article","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T18:20:33Z","timestamp":1754590833000},"page":"2481-2494","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Neuromelanin-induced cellular stress and neurotoxicity in the pathogenesis of Parkinson's disease"],"prefix":"10.1007","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8216-1171","authenticated-orcid":false,"given":"Md.","family":"Jakaria","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1907-4555","authenticated-orcid":false,"given":"Jason R.","family":"Cannon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,7]]},"reference":[{"key":"2156_CR1","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.pneurobio.2005.02.001","volume":"75","author":"H Fedorow","year":"2005","unstructured":"Fedorow H, Tribl F, Halliday G, Gerlach M, Riederer P, Double KL (2005) Neuromelanin in human dopamine neurons: comparison with peripheral melanins and relevance to Parkinson\u2019s disease. 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