Nutrient deficiency-induced downregulation of SNX1 inhibits ferroptosis through PPARs-ACSL1/4 axis in colorectal cancer

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.