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In this study, we report that wild\u2010type PDI, through its specific interaction with TDP\u201043, markedly attenuates phase separation of TDP\u201043, competitively displaces G3BP1 to disassemble TDP\u201043\/G3BP1 condensates, and further counteracts the pathological mislocalization, abnormal phosphorylation, and pathological aggregation of TDP\u201043 through the b\u2019 domain of the enzyme. Ultimately, this alleviates mitochondrial damage and neuronal toxicity caused by TDP\u201043 aggregation and suppresses\n                    <jats:italic>UNC13A<\/jats:italic>\n                    cryptic splicing in stressed cells. In the presence of abnormal forms of PDI, however, PDI loses its activity, and stress granules containing TDP\u201043 are assembled into amyloid fibrils, resulting in mitochondrial impairment and neuronal cell death in ALS and AD\u2010TDP patients. These findings not only provide new insights into the pathogenic mechanisms of TDP\u201043 in neurodegenerative diseases such as ALS and AD\u2010TDP, but also propose PDI as a potential therapeutic target.\n                  <\/jats:p>","DOI":"10.1002\/advs.202516846","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T07:35:21Z","timestamp":1779694521000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Protein Disulfide Isomerase Disassembles TDP\u201043\/G3BP1 Condensates and Antagonizes TDP\u201043 Pathological Aggregates"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4783-9099","authenticated-orcid":false,"given":"Jia\u2010Qi","family":"Liu","sequence":"first","affiliation":[{"name":"Hubei Key Laboratory of Cell Homeostasis College of Life Sciences Wuhan University  Wuhan 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