Rigosertib promotes ferroptosis in colorectal cancer by increasing Keap1, reducing Nrf2/SLC7A11 signaling, and facilitating autophagic GPX4 degradation.

Abstract

Colorectal cancer (CRC) ranks among the leading malignancies worldwide in both incidence and mortality, and its treatment continues to face major challenges such as chemoresistance and tumor metastasis. This study aims to investigate the potential therapeutic value and underlying mechanisms of the multikinase inhibitor Rigosertib (Rig) in CRC. Our findings demonstrate that Rig markedly suppresses the proliferation, migration, and invasion of CRC cells while inducing apoptosis. Transcriptomic analyses suggest that ferroptosis may be involved in Rig's antitumor activity. Subsequent experiments confirm that Rig induces typical features of ferroptosis. Mechanistically, Rig exerts its effects through a dual regulatory mechanism. On one hand, it upregulates Keap1 expression, thereby suppressing the Nrf2/SLC7A11 signaling pathway and weakening the cellular antioxidant defense. On the other hand, Rig enhances autophagic flux, promoting the autophagy-lysosome-dependent degradation of GPX4, a key regulator of ferroptosis. Notably, both the Nrf2 pathway agonist KI696 and the autophagy inhibitor 3-methyladenine partially reverse Rig-induced ferroptosis, while GPX4 overexpression markedly attenuates Rig's cytotoxicity, confirming the crucial roles of these pathways in its mechanism of action. Moreover, Rig exhibits a pronounced synergistic antitumor effect with 5-fluorouracil in vitro. In xenograft mouse models, Rig treatment effectively suppresses tumor growth without causing significant systemic toxicity. This study, for the first time, reveals that Rig induces ferroptosis through dual mechanisms involving coordinated regulation of the Keap1/Nrf2/SLC7A11 axis and autophagy-dependent degradation of GPX4. These findings provide a novel theoretical foundation and a promising therapeutic strategy for colorectal cancer treatment.

Key Findings

• Rigosertib suppresses colorectal cancer cell proliferation, migration, and invasion while inducing apoptosis.
• Rigosertib induces ferroptosis by upregulating Keap1, suppressing Nrf2/SLC7A11 signaling, and promoting autophagic degradation of GPX4.
• Combination of Rigosertib with 5-fluorouracil shows synergistic antitumor effects in vitro and effectively suppresses tumor growth in xenograft models without significant toxicity.

Clinical Significance

Citation

Shi Yongkang, Lu Qiliang, Wang Ziweiet al.. Rigosertib promotes ferroptosis in colorectal cancer by increasing Keap1, reducing Nrf2/SLC7A11 signaling, and facilitating autophagic GPX4 degradation. Cellular signalling. 2026-Nov-07.