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The impact of CAF-derived circKLHL24 on perineural invasion (PNI) in tumor cells was evaluated both in vitro and in vivo. RNA sequencing, RNA pulldown, RNA immunoprecipitation, and luciferase reporter assays were conducted to identify downstream targets and elucidate the underlying mechanism of circKLHL24 in PNI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>CircKLHL24 (hsa_circ_0001369), a CAF-specific circRNA, is associated with PNI and poor survival in advanced PDAC. Silencing or overexpressing circKLHL24 in CAFs altered the ability of CAFs to induce tumor cell invasion and nerve infiltration via chemokine (C-X-C Motif) ligand 12 (CXCL12). Mechanistically, first, circKLHL24 binds to the membrane protein Sec31A, inhibiting its ubiquitination and degradation, thereby enhancing CXCL12 secretion. Second, circKLHL24 acts as a sponge for miR-615-5p, relieving its suppression of CXCL12 mRNA and amplifying CXCL12 expression. Moreover, high circKLHL24 levels were positively correlated with elevated serum CXCL12 levels in PDAC and poor patient survival. Targeting circKLHL24 or neutralizing CXCL12 suppresses PDAC invasion and neuronal recruitment in nude mouse and KPC models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The circKLHL24\/Sec31A\/miR-615-5p\/CXCL12 axis is critical for CAF-induced PNI in PDAC. Therefore, circKLHL24 could serve as a potential therapeutic target for PDAC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-025-03489-2","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T04:43:37Z","timestamp":1759812217000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Cancer-associated fibroblast-derived circKLHL24 drives perineural invasion in pancreatic cancer via dual regulation of the sec31a-CXCL12 axis"],"prefix":"10.1186","volume":"44","author":[{"given":"Tingting","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rihua","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianhao","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honghui","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huimou","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shangyou","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chonghui","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shizong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guolin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rufu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,7]]},"reference":[{"key":"3489_CR1","first-page":"10","volume":"75","author":"RL Siegel","year":"2025","unstructured":"Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. 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All animal experiments (Approval No.:KY2024-999-01) conducted was compliant with the Ethical Committee of Guangdong Provincial People\u2019s Hospital. Our study utilized survival analysis data from a previously published randomized controlled trial (RCT), which had received ethical approval from the Ethical Committee of Guangdong Provincial People\u2019s Hospital. This study involves only secondary data analysis and does not include the recruitment of new patients.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors give consent for publication of the manuscript.","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":"281"}}