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Here, we present a comprehensive proteomic and biochemical characterization of the Amazonian chactid scorpion Brotheas amazonicus venom (BamazV), with emphasis on molecular complexity, proteolytic processing, and peptide diversity. Using an integrative venomics approach that combines molecular mass-based fractionation, reversed-phase chromatography, high-resolution mass spectrometry, N-terminal sequencing, and functional and immunological analyses, we reveal an unexpectedly complex venom profile enriched in high-molecular-weight components and extensively processed peptides, with more than 40 venom peptides sequenced by MS\/MS and Edman degradation. The data provide evidence for non-canonical proteolytic events, including the generation of peptides from precursor regions not classically associated with mature venom components. In contrast to the venom of Tityus serrulatus, BamazV displays a \u201chydrolase-rich, neurotoxin-poor\u201d profile, featuring a catalytically active Group III phospholipase A2 (BamazPLA2), a highly active hyaluronidase, metalloproteases, low-mass peptides, and potassium channel toxins. Our results suggest a hydrolytic prey-subjugation strategy, and limited cross-reactivity with commercial antivenom highlighted its distinct structural landscape. Overall, this study advances the understanding of venom evolution and proteolytic diversification in underexplored scorpion lineages, positioning B. amazonicus as a valuable model for investigating alternative venom strategies and identifying novel biotechnological scaffolds.<\/jats:p>","DOI":"10.3390\/ijms27031475","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T12:49:44Z","timestamp":1770036584000},"page":"1475","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Hydrolase-Rich Venom Beyond Neurotoxins: Integrative Functional Proteomic and Immunoreactivity Analyses Reveal Novel Peptides in the Amazonian Scorpion Brotheas amazonicus"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9791-0630","authenticated-orcid":false,"given":"Gisele Adriano","family":"Wiezel","sequence":"first","affiliation":[{"name":"Department of BioMolecular Sciences, School of Pharmaceutical Sciences of Ribeir\u00e3o Preto, University of S\u00e3o Paulo, Ribeir\u00e3o Preto 14040-903, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6540-2295","authenticated-orcid":false,"given":"Karla de Castro Figueiredo","family":"Bordon","sequence":"additional","affiliation":[{"name":"Department of BioMolecular Sciences, School of Pharmaceutical Sciences of Ribeir\u00e3o Preto, University of S\u00e3o Paulo, Ribeir\u00e3o Preto 14040-903, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonas Gama","family":"Martins","sequence":"additional","affiliation":[{"name":"Graduate Program in Genetics, Conservation and Evolutionary Biology (PPG GCBEv), National Institute for Amazon Research (INPA), Manaus 69067-375, AM, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Viviane Imaculada do Carmo","family":"Cust\u00f3dio","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, Ribeir\u00e3o Preto 14049-900, SP, Brazil"},{"name":"Barao de Maua University Center, Ribeir\u00e3o Preto 14090-180, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3491-1641","authenticated-orcid":false,"given":"Alessandra Kimie","family":"Matsuno","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo, Ribeir\u00e3o Preto 14049-900, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8538-4642","authenticated-orcid":false,"given":"Rudi Emerson de Lima","family":"Proc\u00f3pio","sequence":"additional","affiliation":[{"name":"Graduate Program in Biotechnology and Natural Resources of Amazon, University of the State of Amazonas (UEA), Manaus 69065-001, AM, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6712-6033","authenticated-orcid":false,"given":"Eliane Candiani","family":"Arantes","sequence":"additional","affiliation":[{"name":"Department of BioMolecular Sciences, School of Pharmaceutical Sciences of Ribeir\u00e3o Preto, University of S\u00e3o Paulo, Ribeir\u00e3o Preto 14040-903, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fevo.2019.00196","article-title":"Venom costs and optimization in scorpions","volume":"7","author":"Evans","year":"2019","journal-title":"Front. 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