Multiomic traits reveal critical irinotecan-related regulators in colorectal cancer, and irinotecan promotes ferroptosis in colorectal cancer by regulating FSTL3

Abstract Background： Irinotecan is a widely used chemotherapy drug in colorectal cancer (CRC). The evolution and prognosis of CRC involve complex mechanisms and depend on the drug administered, especially for irinotecan. We aim to explore the specific mechanism and multiomic traits of irinotecan-related regulators, which is beneficial for accurate individualized treatment for CRC. Methods: Bioinformatics analysis was used to explore the multiomic traits of irinotecan-related regulators. RT‒qPCR, western blotting and flow cytometry were used as experimental validations. Results: Iriscore (irinotecan-related score) was constructed based on irinotecan-related regulators and a high iriscore predicted a poor prognosis, poor therapeutic response and the MSS/MSI-L status. Single-cell analysis revealed that FSTL3 and TMEM98 were mainly expressed in CRC stem cells. Potential transcription factors (E2F1, STAT1, and TTF2) and therapeutic drugs (telatinib) that target irinotecan-related regulators were identified. FSTL3 was the core risk irinotecan-related regulator. Some ferroptosis regulators (GPX4, HSPB1 and RGS4) and related metabolic pathways (lipid oxidation and ROS metabolism) were correlated significantly with FSTL3. In vitro, irinotecan inhibited the expression of FSTL3 and ferroptotic defence proteins (GPX4 and SLC7A11) and induced lipid peroxidation. Conclusion: We confirmed irinotecan-related regulators, especially FSTL3, have effective prognostic value in CRC and showed that irinotecan promotes ferroptosis by inhibiting FSTL3, which is beneficial for identifying candidate targeted irinotecan-related regulators and accurate individualized treatment strategies for CRC.