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While UPR's role in viral infections has been well documented, recent studies indicate that intracellular bacterial pathogens have evolved specific mechanisms to hijack UPR signaling for survival and replication. This review examines UPR manipulation strategies employed by major bacterial pathogens, including\n                    <jats:italic>Brucella<\/jats:italic>\n                    ,\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    <\/jats:styled-content>\n                    ,\n                    <jats:italic>Legionella<\/jats:italic>\n                    , and\n                    <jats:italic>Salmonella<\/jats:italic>\n                    . These pathogens utilize effector proteins that target specific UPR components:\n                    <jats:italic>Brucella<\/jats:italic>\n                    effectors VceC, BspB, TcpB, and BspL interact with ER chaperones and ERAD machinery;\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>M.\u2009tuberculosis<\/jats:italic>\n                    <\/jats:styled-content>\n                    proteins Rv0297, ESAT\u20106, HBHA, and CdhM disrupt calcium homeostasis and alter ER morphology;\n                    <jats:italic>Legionella<\/jats:italic>\n                    Lpg0519 activates atypical ATF6 signaling; and bacterial toxins including cholera toxin bind IRE1\u03b1 structural motifs for pathway activation. The molecular basis of UPR manipulation includes direct protein\u2013protein interactions, calcium signaling interference, ER morphological disruption, and transcriptional program modulation. Bacterial hijacking of UPR pathways affects ER\u2010phagy processes and host immune responses, facilitating intracellular survival. UPR pathway components serve as potential targets for host\u2010directed therapy against persistent and drug\u2010resistant infections. Small molecule modulators targeting IRE1\u03b1 kinase activity, PERK inhibitors, and ATF6 pathway regulators may complement conventional antimicrobial approaches. Characterization of these host\u2010pathogen interactions provides insights for developing therapeutic strategies that target bacterial dependencies on cellular stress responses.\n                  <\/jats:p>","DOI":"10.1096\/fj.202503547r","type":"journal-article","created":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T09:42:08Z","timestamp":1768642928000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Manipulation of the Unfolded Protein Response by Intracellular Bacterial Pathogens: Mechanisms of ER Hijacking and Therapeutic Implications"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3682-6667","authenticated-orcid":false,"given":"Enhui","family":"Dai","sequence":"first","affiliation":[{"name":"Institute of Animal Science, Chinese Academy of Agricultural Sciences  Beijing China"},{"name":"College of Veterinary Medicine Shandong Agricultural University  Taian 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