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Through subclone screening and characterization, we identified that the loss of Ig production impaired the recognition ability of hapten\u2010specific hybridomas. Proteomic analysis further highlighted the critical role of the unfolded protein response (UPR) pathway in regulating aberrant Ig chain production. Using CRISPR\/Cas9\u2010mediated knockout and rescue experiments, we revealed the importance of the UPR pathway in facilitating hybridoma antibody production by targeting\n                    <jats:italic>Xbp1<\/jats:italic>\n                    s, an active transcription factor downstream of UPR signaling. With CRISPR\/HDR, we inserted a fluorescent mGFP tag into the endogenous\n                    <jats:italic>Hspa5<\/jats:italic>\n                    gene (encoding BiP, the master regulator of the UPR pathway), enabling in situ and real\u2010time monitoring of UPR activation. A strong negative correlation (R\n                    <jats:sup>2<\/jats:sup>\n                    = 0.86) was observed between intracellular mGFP signals and IgG levels in the engineered system, indicating a close relationship between UPR activation and Ig production. Fluorescence\u2010activated cell sorting of high\u2010mGFP populations identified two dysfunctional subclones that failed to secret Ig, validating the system\u2019s effectiveness in tracing Ig homeostasis. In summary, this study provides new insights into UPR\u2010mediated regulation of Ig synthesis and offers a novel UPR\u2010based reporter system for monitoring antibody stability.\n                  <\/jats:p>","DOI":"10.1002\/advs.202514140","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T05:55:52Z","timestamp":1768974952000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Quantitative Proteomics and CRISPR\/Cas9 Editing Reveal UPR\u2010Mediated Control of Immunoglobulin Homeostasis in Hybridomas"],"prefix":"10.1002","volume":"13","author":[{"given":"Rubing","family":"Zou","sequence":"first","affiliation":[{"name":"Institute of Pesticide and Environmental Toxicology Zhejiang Key Laboratory of Biology and Ecological Regulation of Crop Pathogens and Insects Ministry of Agriculture and Rural Affairs Key Laboratory of Molecular Biology of Crop Pathogens and Insect Pests Zhejiang 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Clinical Medicine Zhejiang Provincial People's Hospital of Hangzhou Medical College  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guonian","family":"Zhu","sequence":"additional","affiliation":[{"name":"Institute of Pesticide and Environmental Toxicology Zhejiang Key Laboratory of Biology and Ecological Regulation of Crop Pathogens and Insects Ministry of Agriculture and Rural Affairs Key Laboratory of Molecular Biology of Crop Pathogens and Insect Pests Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Seong","family":"Lee","sequence":"additional","affiliation":[{"name":"Graduate School of Engineering Biology KAIST  Daejeon Republic of Korea"},{"name":"KI for the BioCentury KAIST  Daejeon Republic of 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