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Serine\/threonine protein kinase 25 (STK25) exerts multiple roles in tumourigenesis; however, its role in mediating tumour\u2013stroma crosstalk remains largely unexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Primary CAFs were isolated from CRC patient tissues and characterised to confirm their identity. The effects of STK25 expression on CAF activity and CAF\u2010mediated tumour progression were evaluated both in vitro and in vivo. Western blot, qRT\u2010PCR, ChIP and dual\u2010luciferase reporter assays were performed to elucidate the mechanism by which STK25 regulated CAF activation. Moreover, the effect of STK25 expression on CAF\u2010induced cetuximab resistance was assessed in vitro and in vivo. The clinical significance of STK25 expression was determined in CRC patient tissues, tissue microarrays and patient\u2010derived organoids.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Knockdown of STK25 in CRC cells enhanced CAF proliferation, migration and activation, whereas its overexpression exhibited the opposite effect. STK25\u2010knockdown\u2010mediated CAF activation subsequently promoted CRC cell proliferation and metastasis. Moreover, STK25 depletion combined with CAFs significantly enhanced CRC tumour growth in vivo. Mechanistically, STK25 deficiency activated the NF\u2010\u03baB pathway, leading to p50 phosphorylation which directly bound to the AREG promoter, thereby transcriptionally up\u2010regulating AREG expression. In addition, STK25\u2010regulated AREG\/EGFR axis mediated the crosstalk between CRC cells and CAFs. More importantly, CAFs conferred resistance to the anti\u2010EGFR antibody cetuximab, which could be reversed either by STK25 overexpression or by AREG\u2010neutralising antibody treatment. Clinically, low STK25 expression correlated with elevated CAFs marker levels and poor cetuximab response in CRC patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings identified STK25 as a critical regulator of the NF\u2010\u03baB\/AREG\/EGFR axis in tumour\u2013CAF communication and highlight its potential as a therapeutic target for overcoming CAF\u2010induced cetuximab resistance in CRC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>STK25 deficiency enhanced CAF\u2010mediated CRC growth via the NF\u2010\u03baB\/AREG\/EGFR axis.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>STK25 overexpression or AREG antibody overcame CAF\u2010mediated cetuximab resistance.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>CRC patients with high STK25 and low CAFs marker levels might benefit from cetuximab treatment.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70678","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T05:36:57Z","timestamp":1777527417000},"source":"Crossref","is-referenced-by-count":1,"title":["STK25 inhibits cancer\u2010associated fibroblast activation to overcome cetuximab resistance in colorectal cancer"],"prefix":"10.1002","volume":"16","author":[{"given":"Yifan","family":"Hou","sequence":"first","affiliation":[{"name":"Key Laboratory of Carcinogenesis 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Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV Peking University Cancer Hospital &amp; Institute  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Song","sequence":"additional","affiliation":[{"name":"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV Peking University Cancer Hospital &amp; Institute  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pu","family":"Xing","sequence":"additional","affiliation":[{"name":"Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV Peking University Cancer Hospital &amp; Institute  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Weng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Carcinogenesis and Translational Research 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