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Here, we report that Sel-1 Suppressor of Lin-12-Like 3 (SEL1L3) protein resided on the ER membrane can effectively prevent HRD1-mediated ERAD process via dual mechanisms: SEL1L3 disrupts SEL1L-HRD1 complex by mutually exclusively interacting with SEL1L and HRD1 respectively, resulting in concomitant prevention of substrate degradation; on the other hand, SEL1L3 can accelerate HRD1 protein degradation. Biologically, SEL1L3 inhibits colorectal cancer (CRC) cell growth and migration, which counteracts the oncogenic activity of HRD1; moreover, we identify STING as a HRD1 substrate and a critical downstream effector mediating tumor suppression activity of SEL1L3. Collectively, these data demonstrate that SEL1L3 is a critical regulator of ERAD and exerts a potent tumor-suppressing function, and that the SEL1L3\/HRD1\/STING axis plays a crucial role in CRC growth and migration.<\/jats:p>","DOI":"10.1038\/s41419-026-08770-6","type":"journal-article","created":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T03:03:25Z","timestamp":1777777405000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["SEL1L3 suppresses colorectal cancer cell growth and metastasis by preventing endoplasmic reticulum-associated degradation of STING"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2767-1997","authenticated-orcid":false,"given":"Hui","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2403-3328","authenticated-orcid":false,"given":"Wenli","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4699-5010","authenticated-orcid":false,"given":"Mengying","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuqun","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keyan","family":"Miao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengjiang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiali","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiamin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixia","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1856-6013","authenticated-orcid":false,"given":"Hao","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0634-2020","authenticated-orcid":false,"given":"Zhaoyuan","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,3]]},"reference":[{"key":"8770_CR1","doi-asserted-by":"crossref","unstructured":"Lak B, Li S, Belevich I, Sree S, Butkovic R, Ikonen E, et al. 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