Qian Li-Heng, Wen Kai-Ling, Guo Ying, Liao Ying-Na, Li Ming-Yue, Li Zuo-Qing, Li Shu-Xin, Nie Hui-Zhen
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
Radiology Department, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, China.
Apoptosis. 2025 Mar 17. doi: 10.1007/s10495-025-02088-y.
Colorectal cancer (CRC) is among the most prevalent and deadly gastrointestinal malignancies, with advanced-stage tumors often exhibiting resistance to both chemotherapy and targeted therapies, underscoring the urgent need for novel therapeutic targets to improve clinical outcomes. Sorting nexin 1 (SNX1), previously implicated in receptor trafficking between early and late endosomes/lysosomes in cancer studies, has an unclear role in CRC tumorigenesis and progression. Our study revealed that SNX1 expression was downregulated in CRC, and its low levels correlated with advanced tumor stages and unfavorable clinical outcomes. Functionally, SNX1 significantly inhibited tumor cell growth both in vitro and in vivo. Further experiments showed that SNX1 induced ferroptosis in CRC cells by modulating the PPARs-ACSL1/4 pathway downstream of EGFR signaling. Moreover, glucose deprivation suppressed the Hippo pathway, promoted YAP nuclear translocation, and activated the transcription factor Yin Yang 1 (YY1), leading to SNX1 downregulation. This subsequently activated EGFR signaling and ultimately suppressed ferroptosis in CRC cells. Notably, the combination of SNX1 overexpression and 5-fluorouracil (5-FU) treatment exhibited a synergistic anti-tumor effect in a cell-derived xenograft (CDX) model. These findings underscore the critical role of SNX1 in regulating ferroptosis and tumor progression in CRC and highlight its potential as a therapeutic target to enhance chemotherapy effectiveness in CRC.
结直肠癌（CRC）是最常见且致命的胃肠道恶性肿瘤之一，晚期肿瘤通常对化疗和靶向治疗均表现出耐药性，这凸显了迫切需要新的治疗靶点以改善临床结局。分选连接蛋白1（SNX1）在癌症研究中先前被认为参与早期和晚期内体/溶酶体之间的受体转运，但其在结直肠癌发生和发展中的作用尚不清楚。我们的研究表明，SNX1在结直肠癌中表达下调，其低水平与肿瘤晚期和不良临床结局相关。在功能上，SNX1在体外和体内均显著抑制肿瘤细胞生长。进一步实验表明，SNX1通过调节表皮生长因子受体（EGFR）信号下游的过氧化物酶体增殖物激活受体（PPARs）-长链脂肪酸辅酶A合成酶1/4（ACSL1/4）途径诱导结直肠癌细胞发生铁死亡。此外，葡萄糖剥夺抑制了Hippo信号通路，促进Yes相关蛋白（YAP）核转位，并激活转录因子阴阳1（YY1），导致SNX1下调。这随后激活了EGFR信号，最终抑制了结直肠癌细胞的铁死亡。值得注意的是，在细胞来源的异种移植（CDX）模型中，SNX1过表达与5-氟尿嘧啶（5-FU）治疗联合显示出协同抗肿瘤作用。这些发现强调了SNX1在调节结直肠癌铁死亡和肿瘤进展中的关键作用，并突出了其作为增强结直肠癌化疗疗效的治疗靶点的潜力。
