A novel recombinant peptide, rAnguillin, induces ferroptosis in nasopharyngeal carcinoma by promoting FOXM1 degradation and disrupting the FOXM1-PABPC1L-tryptophan metabolism axis

Nasopharyngeal carcinoma (NPC) is a highly aggressive malignancy. Given conventional therapy limitations, exploring non-apoptotic pathways like Ferroptosis is crucial. Tryptophan (Trp) metabolic reprogramming is a key mechanism by which NPC cells evade Ferroptosis by maintaining redox homeostasis. In this study, we investigated the anti-NPC activity of rAnguillin, a novel recombinant peptide derived from Anguilla anguilla, and elucidated the molecular mechanisms by which it induces Ferroptosis via the FOXM1/PABPC1L axis. rAnguillin (7009 Da) was prepared via prokaryotic expression, with its primary sequence verified by LC-MS/MS. Notably, rAnguillin significantly inhibited NPC cell proliferation (IC₅₀ = 3.306 μM at 24 h) and suppressed xenograft tumor growth in vivo in a dose-dependent manner. Mechanistically, as validated by CETSA and site-directed mutagenesis, rAnguillin directly interacted with the transcription factor FOXM1, triggering its ubiquitin-proteasome-dependent degradation. The downregulation of FOXM1 inhibited the transcriptional activation of PABPC1L, subsequently leading to the inactivation of the JAK2-STAT1 signaling axis. This cascade significantly suppressed the expression of rate-limiting Enzymes such as IDO1, thereby depleting the tryptophan metabolic flux and the antioxidant protective effects of its metabolite, 3-hydroxyanthranilic acid (3-HAA). Ultimately, this disruption of redox homeostasis triggered robust Ferroptosis, as evidenced by TEM and inhibitor rescue experiments. Taken together, this study demonstrates that rAnguillin induces Ferroptosis in NPC cells by targeting FOXM1 for degradation, which subsequently suppresses the FOXM1-PABPC1L-JAK2/STAT1-tryptophan metabolism axis. These findings provide a promising therapeutic strategy and a potent drug candidate for the treatment of NPC.