HNRNPC reprograms cancer metabolism to drive acquired chemoresistance in colorectal cancer by repressing of Nrf2/SLC7A11-dependent ferroptosis.

Chemotherapeutic efficacy in colorectal cancer (CRC) is primarily driven‌ by adaptive mechanisms that circumvent therapy-induced ferroptosis. Despite the established role of ROS-mediated lipid peroxidation in initiating ferroptosis, the molecular regulators enabling cancer cells to escape this iron-dependent demise remain elusive. Here, we ‌identify‌ Heterogeneous Nuclear Ribonucleoprotein C (HNRNPC) as a critical orchestrator of chemoresistance in CRC via metabolic reprogramming of ferroptosis pathways. ‌Clinically, elevated HNRNPC expression correlates with poor chemotherapy outcomes‌ by conferring resistance to irinotecan (CPT-11). Mechanistically, HNRNPC augments the Nrf2/SLC7A11 axis-associated transcript stability by shielding Nrf2 and SLC7A11 mRNAs from degradation machinery, thereby enhancing the longevity of their RNAs. Concurrently, HNRNPC forms a direct protein interactome with ferroptosis gatekeepers Nrf2 and SLC7A11, enforcing the post-translational stabilization of these cytoprotective effectors. This bimodal regulation establishes HNRNPC as a master ferroptosis suppressor that drives acquired chemoresistance through redox homeostasis reprogramming in colorectal carcinogenesis, thereby enhancing cellular redox buffering capability. This RNA–protein interaction amplifies the Nrf2/SLC7A11 signaling axis, which scavenges lethal lipid peroxides and attenuates CPT-11 cytotoxicity. Genetic depletion or pharmacological inhibition of HNRNPC restored ferroptotic vulnerability and resensitized CRC models to chemotherapy. Our findings establish HNRNPC as a post-transcriptional regulator of ferroptosis defense and reveal a therapeutic strategy for overcoming chemoresistance by co-targeting HNRNPC in CRC‌‌. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-025-02577-2.