Ionizing radiation (IR) poses a dual challenge in medicine; while essential for cancer therapy, it inflicts collateral damage to normal tissues, particularly the gastrointestinal (GI) tract. High-dose IR triggers acute radiation syndrome (ARS), characterized by crypt stem cell depletion, mucosal barrier disruption, inflammation, and potential progression to fibrosis and secondary malignancy. Emerging evidence identifies the epithelial kinase doublecortin-like kinase 1 (DCLK1)—highly expressed in GI tuft cells and cancer stem-like cells—as a master regulator of post-IR responses. DCLK1 integrates DNA repair (via p53/ATM), and survival signaling (via NF-κB, TGF-β, and MAPK) to promote epithelial regeneration, yet these same mechanisms contribute to therapy resistance and oncogenesis. DCLK1 further modulates the immune microenvironment by skewing macrophages toward an immunosuppressive M2 phenotype, enhancing tissue remodeling, angiogenesis, and immune evasion. Preclinical studies demonstrate that DCLK1 inhibition sensitizes tumors to radiotherapy while preserving mucosal repair. Therapeutic strategies targeting DCLK1, alongside radioprotective agents, immunomodulators, and senolytics, may enhance regeneration, limit fibrosis, and eradicate therapy-resistant cancer stem cells. This review highlights DCLK1’s dual role in regeneration and tumorigenesis and evaluates its potential as a therapeutic target and biomarker in IR-induced GI damage.
电离辐射在医学领域面临双重挑战：作为癌症治疗的关键手段，它同时会对正常组织造成附带损伤，尤其影响胃肠道。高剂量辐射会引发急性放射综合征，其特征包括隐窝干细胞耗竭、黏膜屏障破坏、炎症反应，并可能进展为纤维化和继发性恶性肿瘤。最新研究发现，上皮激酶双皮质素样激酶1——在胃肠道簇细胞和癌症干细胞样细胞中高表达——是辐射后反应的核心调控因子。DCLK1通过整合DNA修复通路（经p53/ATM介导）和生存信号通路（经NF-κB、TGF-β及MAPK介导）促进上皮再生，但这些机制同时导致治疗抵抗和肿瘤发生。DCLK1还能通过促使巨噬细胞向免疫抑制性M2表型极化，进而调控免疫微环境，增强组织重塑、血管生成和免疫逃逸能力。临床前研究表明，抑制DCLK1可在保护黏膜修复的同时增强肿瘤对放疗的敏感性。针对DCLK1的治疗策略，结合放射防护剂、免疫调节剂和衰老细胞清除剂，有望促进组织再生、限制纤维化并清除治疗抵抗性癌症干细胞。本文综述了DCLK1在组织再生与肿瘤发生中的双重作用，并评估其作为电离辐射所致胃肠道损伤治疗靶点与生物标志物的潜力。
肿瘤(癌症)患者之家