{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T11:26:46Z","timestamp":1788348406225,"version":"build-2803163510"},"reference-count":51,"publisher":"National Academy of Sciences","issue":"48","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81773203"],"award-info":[{"award-number":["81773203"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82470189"],"award-info":[{"award-number":["82470189"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81970182"],"award-info":[{"award-number":["81970182"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,12,2]]},"abstract":"<jats:p>\n                    Ubiquitin-specific peptidase 1 (USP1) plays a critical role in the progression and chemoresistance of various cancers, making USP1 inhibitors a promising therapeutic option in cancer treatment. However, the role of USP1 in peripheral T-cell lymphoma (PTCL) has remained unexplored. Our study uncovers a USP1-dependent survival axis driving chemoresistance in PTCL. USP1 is significantly upregulated in PTCL patients and correlates with poor prognosis through promoting mortalin degradation via TRAF2 deubiquitination.\n                    <jats:italic toggle=\"yes\">USP1<\/jats:italic>\n                    overexpression enhances TRAF2 stability by reducing its ubiquitination, thereby elevating TRAF2 levels. This, in turn, facilitates mortalin degradation, leading to diminished mortalin expression, reduced mitochondrial localization of mortalin, and impaired apoptosis. Notably, silencing\n                    <jats:italic toggle=\"yes\">mortalin<\/jats:italic>\n                    in PTCL cells further decreases sensitivity to doxorubicin and suppresses apoptotic pathways. Mechanistically, reduced mitochondrial localization of mortalin disrupts calcium transport between the endoplasmic reticulum and mitochondria through the IP\n                    <jats:sub>3<\/jats:sub>\n                    R\u2013mortalin\u2013VDAC1 complex. The impaired calcium shuttling triggers the activation of NF-\u03baB and JAK-STAT signaling pathways, ultimately attenuating apoptosis. Importantly, pharmacological inhibition of USP1 with ML323 effectively enhances PTCL cell sensitivity to doxorubicin, suggesting a promising therapeutic strategy to improve treatment outcomes in PTCL patients. Collectively, we have found that USP1 represents a compelling therapeutic target for addressing chemoresistance and improving outcomes in PTCL therapy.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2504195122","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T19:02:44Z","timestamp":1764097364000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":4,"title":["USP1\u2013TRAF2 axis\u2013regulated mortalin stability mediates chemoresistance by disrupting calcium transport in peripheral T-cell lymphoma"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-1874-5612","authenticated-orcid":false,"given":"Ailing","family":"Gui","sequence":"first","affiliation":[{"name":"Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University","place":["Shanghai, 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