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The natural compound Deoxyshikonin (DSHK) has shown promising anti-tumor potential. However, the anti-CRC effects of DSHK and its molecular target remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The anti-CRC efficacy of DSHK was evaluated using human CRC cell lines, patient-derived organoids (PDOs), cell line-derived xenograft (CDX), and patient-derived organoid xenograft (PDOX) models. Target identification involved chemical proteomics, CETSA, SPR, and molecular dynamics simulations. Protein interactions were probed using SPIDER proximity labeling, Co-IP, GST pull-down, and confocal microscopy. The spatial distribution of interacting proteins was examined through high-density tissue microarrays, and functional pathways were explored via whole-transcriptome sequencing, rMATS, and ultrastructural imaging.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>DSHK demonstrated potent antitumor efficacy in preclinical models of CRC. HSPA8 was identified as the direct molecular target of DSHK. Moreover, the anti-CRC effect of DSHK depended on HSPA8. Additionally, GEMIN5 was identified as a novel functional interactor of HSPA8 in CRC pathogenesis. The expression levels and co-localization intensity of HSPA8 and GEMIN5 were significantly higher in CRC tissues compared to adjacent normal tissues. Moreover, DSHK destabilized the oncogenic HSPA8-GEMIN5 complex, thereby triggering aberrant splicing of ribosomal protein-coding genes mediated by GEMIN5, thereby impeding functional ribosome biogenesis. Concomitantly, DSHK impaired HSPA8-mediated initiation factors interaction and destabilized the eIF4F complex, resulting in dysfunctional translation initiation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>DSHK targeted the HSPA8-GEMIN5 interaction interface to impair ribosome biogenesis and dysregulating translation initiation to suppress protein synthesis. This study established the newly identified HSPA8-GEMIN5 complex as a molecular hub mediating \u201csplicing-translation coupling\u201d in CRC and provided a novel \u201cdual-pathway intervention targeting splicing and translation\u201d strategy inducing proteostasis imbalance for CRC therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-026-03645-2","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:28:21Z","timestamp":1768566501000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Disruption of HSPA8-GEMIN5 interaction suppresses colorectal cancer by impaired splicing-translation coupling-mediated proteostasis imbalance"],"prefix":"10.1186","volume":"45","author":[{"given":"Fei","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiming","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoxin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejiao","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuguo","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufeng","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanying","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfei","family":"Tu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongdong","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,16]]},"reference":[{"key":"3645_CR1","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1038\/s41571-025-01037-7","volume":"22","author":"MA McCabe","year":"2025","unstructured":"McCabe MA, Mauro AJ, Schoen RE. 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All participants provided written informed consent. Commercial Colorectal cancer tissue microarrays were purchased from Hunan Aifang Biotechnology Co. (Ethics Statement Number: Csyayj2024075). All experiments involving animals were conducted according to the ethical policies and procedures approved by the ethics committee of Beijing University of Chinese Medicine, China (Approval no. BUCM-2024040109-2022, BUCM-2024062007-2235, BUCM-2025031003-1107).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"47"}}