CSF1 inhibits ferroptosis in colorectal cancer cells by autocrine activation of the JAK/STAT3 signaling pathway.
Colorectal cancer (CRC) remains a major cause of cancer-related mortality, particularly in patients with advanced disease. Although colony stimulating factor 1 (CSF1) has been implicated in tumor progression, its role in CRC remains unclear. In this study, we showed that CSF1 was significantly upregulated in CRC tissues and cell lines, and that high CSF1 expression was associated with adverse clinicopathological features and poorer patient outcomes. Functional assays demonstrated that CSF1 promoted CRC cell proliferation, migration, invasion, and xenograft tumor growth. Importantly, CSF1 also suppressed ferroptosis, as evidenced by reduced reactive oxygen species (ROS) accumulation, lipid peroxidation, malondialdehyde (MDA) production, and Fe2+ levels after CSF1 overexpression, whereas CSF1 knockdown produced the opposite effects. Mechanistically, CRC cells secreted CSF1, as confirmed by enzyme-linked immunosorbent assay (ELISA), and expressed colony stimulating factor 1 receptor (CSF1R), supporting a tumor-cell-intrinsic autocrine CSF1/CSF1R signaling mechanism. This autocrine signaling activated the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway, while blockade of CSF1R or inhibition of JAK/STAT3 signaling reversed CSF1-induced malignant phenotypes and ferroptosis resistance. Further rescue experiments showed that Ferrostatin-1 (Fer-1) alleviated ferroptosis induced by CSF1 knockdown or JAK/STAT3 inhibition. In addition, signal transducer and activator of transcription 3 (STAT3) overexpression upregulated glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase long-chain family member 3 (ACSL3), linking STAT3 activation to anti-ferroptotic effector regulation. Collectively, these findings identify a tumor-cell-derived CSF1/CSF1R-JAK/STAT3 autocrine signaling axis that promotes CRC progression by suppressing ferroptosis, providing a potential therapeutic target for overcoming ferroptosis resistance in CRC.