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However, the physiological mechanisms underlying insect adaptation to natural and synthetic PIs remain poorly understood. Here, we investigated the midgut responses of\n                    <jats:italic>Anticarsia gemmatalis<\/jats:italic>\n                    H\u00fcbner (Lepidoptera: Erebidae) to the soybean Kunitz trypsin inhibitor (SKTI) and the synthetic tripeptide GORE\u20102 using integrated transcriptomic, biochemical, and histological approaches, complemented by an exploratory metatranscriptomic analysis of putative gut\u2010associated microbial transcripts. RNA\u2010seq analysis identified 2542 unique differentially expressed genes (FDR\u2010adjusted\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05, |log2FC\u2009|\u2009\u2265\u20091), including extensive modulation of digestive proteases and redox\u2010related pathways. SKTI induced a compensatory response characterized by the up\u2010regulation of serine proteases, antioxidant enzymes, and detoxification\u2010associated pathways. In contrast, GORE\u20102 promoted broader repression of digestive proteases, including chymotrypsin\u2010 and trypsin\u2010related transcripts and matrix metalloproteinases, together with a distinct antioxidant response. Biochemical assays demonstrated increased CAT, GST, POX, and SOD activities under both treatments. Compared with SKTI, GORE\u20102 induced lower POX, GST, and SOD activities, whereas CAT activity did not differ significantly between the two treatments. Histological analyses demonstrated notable epithelial disruption, vacuolization, and disorganization of the striated border in the larval midgut, with lesion scores being significantly elevated following GORE\u20102 exposure. Exploratory analysis of putative gut\u2010associated microbial transcripts recovered from whole\u2010midgut RNA\u2010seq revealed taxonomically diverse microbial signals associated with carbon metabolism, proteolysis, and detoxification. However, no treatment\u2010associated differential expression was detected among the putative bacterial transcripts. These findings indicate that GORE\u20102 induced broader disruption of digestive and protective midgut functions than SKTI, with weaker antioxidant enzyme induction and more pronounced histological injury, consistent with reduced physiological compensation in\n                    <jats:italic>A. gemmatalis<\/jats:italic>\n                    larvae. These results underscore the potential of synthetic peptide\u2010based protease inhibitors to interfere with adaptive digestive processes in pest insects of agricultural importance.\n                  <\/jats:p>","DOI":"10.1002\/arch.70223","type":"journal-article","created":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T18:22:20Z","timestamp":1791138140000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated Transcriptomic and Physiological Analyses Reveal Disruption of Digestive Homeostasis Induced by Protease Inhibitors in\n                    <i>Anticarsia gemmatalis<\/i>\n                    Caterpillars"],"prefix":"10.1002","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4683-249X","authenticated-orcid":false,"given":"Neilier Rodrigues da Silva","family":"J\u00fanior","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Laboratory of Enzymology and Biochemistry of Proteins and Peptides, Universidade Federal de Vi\u00e7osa, UFV, BIOAGRO\/INCT\u2010IPP Vi\u00e7osa Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1585-8108","authenticated-orcid":false,"given":"Eul\u00e1lio Gutemberg Dias dos","family":"Santos","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Laboratory of Enzymology and Biochemistry of Proteins and Peptides, Universidade Federal de Vi\u00e7osa, UFV, BIOAGRO\/INCT\u2010IPP Vi\u00e7osa Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5790-187X","authenticated-orcid":false,"given":"Daniel Guimar\u00e3es Silva","family":"Paulo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Laboratory of Enzymology and Biochemistry of Proteins and Peptides, Universidade Federal de Vi\u00e7osa, UFV, BIOAGRO\/INCT\u2010IPP Vi\u00e7osa Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5712-9759","authenticated-orcid":false,"given":"Yaremis","family":"Meri\u00f1o\u2010Cabrera","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Laboratory of Enzymology and Biochemistry of Proteins and Peptides, Universidade Federal de Vi\u00e7osa, UFV, BIOAGRO\/INCT\u2010IPP Vi\u00e7osa Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1848-2966","authenticated-orcid":false,"given":"Ian de Paula Alves","family":"Pinto","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Laboratory of Enzymology and Biochemistry of Proteins and Peptides, Universidade Federal de Vi\u00e7osa, UFV, BIOAGRO\/INCT\u2010IPP Vi\u00e7osa Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Julia","family":"Summy","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Laboratory of Enzymology and Biochemistry of Proteins and Peptides, Universidade Federal de Vi\u00e7osa, UFV, BIOAGRO\/INCT\u2010IPP Vi\u00e7osa Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2761-7022","authenticated-orcid":false,"given":"Ian Lucas Batista","family":"Santos","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Laboratory of Enzymology and Biochemistry of Proteins and Peptides, Universidade Federal de Vi\u00e7osa, UFV, BIOAGRO\/INCT\u2010IPP Vi\u00e7osa Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1620-211X","authenticated-orcid":false,"given":"Milena Godoi","family":"Lima","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Laboratory of Enzymology and Biochemistry of Proteins and Peptides, Universidade Federal de Vi\u00e7osa, UFV, BIOAGRO\/INCT\u2010IPP Vi\u00e7osa Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5409-2379","authenticated-orcid":false,"given":"Maria Clara Neves Gomes","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Laboratory of Enzymology and Biochemistry of Proteins and Peptides, Universidade Federal de Vi\u00e7osa, UFV, BIOAGRO\/INCT\u2010IPP Vi\u00e7osa Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3162-7888","authenticated-orcid":false,"given":"Rafael Junior de","family":"Andrade","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Laboratory of Enzymology and Biochemistry of Proteins and Peptides, Universidade Federal de Vi\u00e7osa, UFV, BIOAGRO\/INCT\u2010IPP Vi\u00e7osa Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0477-4252","authenticated-orcid":false,"given":"Jos\u00e9 Eduardo","family":"Serr\u00e3o","sequence":"additional","affiliation":[{"name":"Department of General Biology Universidade Federal de Vi\u00e7osa Vi\u00e7osa Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7986-1369","authenticated-orcid":false,"given":"Elizabeth Pacheco Batista","family":"Fontes","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Laboratory of Plant Molecular Biology Universidade Federal de Vi\u00e7osa, UFV, BIOAGRO\/INCT\u2010IPP Vi\u00e7osa Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6447-8108","authenticated-orcid":false,"given":"Humberto Josu\u00e9 Oliveira","family":"Ramos","sequence":"additional","affiliation":[{"name":"Department of Biochemistry 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