{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPRSS3, also known as mesotrypsin or trypsin‐4, is a unique serine protease that diverges from canonical trypsin isoforms by exhibiting marked resistance to standard trypsin inhibitors and an unusual substrate specificity. Detailed biochemical and structural studies have revealed that single amino acid substitutions—such as the replacement of a conserved glycine with arginine—endow PRSS3 with the capacity to degrade protein inhibitors (e.g., Kunitz‐type inhibitors) while sparing normal zymogen activation pathways. Kinetic and thermodynamic analyses further demonstrated that PRSS3’s reactivity is characterized by the selective cleavage of specific peptide bonds in substrates such as α₁‐antitrypsin and the Kunitz domain of amyloid precursor protein, thereby modulating its inhibitory interactions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the oncologic context, aberrant expression of PRSS3 has been linked to tumor progression, metastasis, and therapeutic resistance in a wide array of human cancers. Multiple studies document that either over‐expression or epigenetic silencing (via promoter hypermethylation) of PRSS3 correlates with aggressive disease features and poor patient prognosis in malignancies including bladder, pancreatic, breast, lung, colon, ovarian, and hepatocellular carcinomas. Notably, PRSS3 has been implicated in driving malignant cell growth and invasion by activating protease‐activated receptors (PARs), modulating matrix degradation, and even cleaving therapeutic antibodies such as cetuximab, thereby contributing to drug resistance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its oncogenic roles, PRSS3 is expressed in normal tissues where it participates in key physiological processes. In neural and epithelial compartments, including the brain and skin, mesotrypsin is involved in regulating proteolytic cascades that influence cell differentiation, barrier formation, and inflammatory responses. For instance, its localized expression in neurons, glial cells, and the epidermal granular layer supports a role in neural function and keratinocyte terminal differentiation, while genetic variants of PRSS3 have been associated with heightened susceptibility to pancreatitis by promoting the degradation of endogenous trypsin inhibitors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, recent investigations have underscored the potential of targeting PRSS3 for therapeutic gain. Owing to its capacity to cleave protective inhibitors and even therapeutic monoclonal antibodies, selective inhibition of mesotrypsin is emerging as a promising strategy to counteract metastasis and overcome drug resistance, as well as to mitigate aberrant proteolytic activity in infectious or inflammatory settings."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "36", "end_ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Gergely Katona, Gunnar I Berglund, Janos Hajdu, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Myelin basic protein, an autoantigen in multiple sclerosis, is selectively processed by human trypsin 4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2005.12.067"}], "href": "https://doi.org/10.1016/j.febslet.2005.12.067"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16412431"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16412431"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Júlia Tóth, Linda Gombos, Zoltán Simon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thermodynamic analysis reveals structural rearrangement during the acylation step in human trypsin 4 on 4-methylumbelliferyl 4-guanidinobenzoate substrate analogue."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M512301200"}], "href": "https://doi.org/10.1074/jbc.M512301200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16492676"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16492676"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Edit Szepessy, Miklós Sahin-Tóth "}, {"type": "b", "children": [{"type": "t", "text": "Human mesotrypsin exhibits restricted S1' subsite specificity with a strong preference for small polar side chains."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS J (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1742-4658.2006.05305.x"}], "href": "https://doi.org/10.1111/j.1742-4658.2006.05305.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16759229"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16759229"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Wolfgang Knecht, Graeme S Cottrell, Silvia Amadesi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Trypsin IV or mesotrypsin and p23 cleave protease-activated receptors 1 and 2 to induce inflammation and hyperalgesia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M703840200"}], "href": "https://doi.org/10.1074/jbc.M703840200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17623652"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17623652"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Moh'd A Salameh, Jessica L Robinson, Duraiswamy Navaneetham, et al. 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