{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T00:03:39Z","timestamp":1782518619038,"version":"3.54.5"},"reference-count":56,"publisher":"American Society for Clinical Investigation","issue":"6","license":[{"start":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T00:00:00Z","timestamp":1742169600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82022051"],"award-info":[{"award-number":["82022051"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82372456"],"award-info":[{"award-number":["82372456"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,3,17]]},"abstract":"<jats:p>\n                    Despite advances in the development of direct KRAS inhibitors, KRAS-mutant cancers continue to exhibit resistance to the currently available therapies. Here, we identified REG\u03b3 as a mutant KRAS\u2013associated factor that enhanced REG\u03b3 transcription through the KRAS intermediate NRF2, suggesting that the REG\u03b3-proteasome is a potential target for pan-KRAS inhibitor development. We elucidated a mechanism involving the KRAS\/NRF2\/REG\u03b3 regulatory axis, which links activated KRAS to the ATP- and ubiquitin-independent proteasome. We subsequently developed RLY01, a REG\u03b3-proteasome inhibitor that effectively suppressed tumor growth in KRAS-mutant cancer models and lung cancer organoids. Notably, the combination of RLY01 and the\n                    <jats:italic>\n                      KRAS\n                      <jats:sup>G12C<\/jats:sup>\n                    <\/jats:italic>\n                    inhibitor AMG510 exhibited enhanced antitumor efficacy in\n                    <jats:italic>\n                      KRAS\n                      <jats:sup>G12C<\/jats:sup>\n                    <\/jats:italic>\n                    cancer cells. Collectively, our data support the hypothesis that KRAS mutations enhance the capacity of the REG\u03b3-proteasome by increasing REG\u03b3 expression, highlighting the potential of ubiquitin-independent proteasome inhibition as a therapeutic approach for pan-KRAS\u2013mutant cancers.\n                  <\/jats:p>","DOI":"10.1172\/jci185278","type":"journal-article","created":{"date-parts":[[2025,3,16]],"date-time":"2025-03-16T14:01:00Z","timestamp":1742133660000},"source":"Crossref","is-referenced-by-count":2,"title":["Targeting ubiquitin-independent proteasome with small molecule increases susceptibility in pan-KRAS\u2013mutant cancer models"],"prefix":"10.1172","volume":"135","author":[{"given":"Shihui","family":"Shen","sequence":"first","affiliation":[{"name":"Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China."},{"name":"Joint Center for Translational Medicine, Shanghai Fifth 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