The novel protein SEMA3C-319aa triggers glutathione metabolism-dependent ferroptosis in gastric cancer

The lack of effective, targeted therapies for gastric cancer (GC) continues to limit patient survival. Circular RNAs (circRNAs), known to act as epigenetic regulators, may also encode functional proteins. In this study, RNA-seq combined with ribosome profiling (Ribo-seq) of human GC cells identified a non-canonically translated circRNA, circSEMA3C, which encodes a novel 319-amino-acid (aa) protein, SEMA3C-319aa. Functionally, both circSEMA3C and SEMA3C-319aa suppressed GC cell viability and tumor growth in vitro and in vivo. Using proteomics and metabolomics, we found that SEMA3C-319aa targets ferroptosis-associated metabolites and metabolic pathways in GC. Notably, SEMA3C-319aa upregulated the production of polyunsaturated fatty acid chains and inhibited glutathione metabolism-particularly the GSH cycle-thereby suppressing GPX4 activity. Mechanistically, SEMA3C-319aa binds to LDHA and, via its non-canonical nuclear localization signal (NLS), sequence shuttles LDHA into the nucleus, where it enhances transcription of the E3 ligase PARK2, promoting GPX4 degradation. Furthermore, combination treatment with SEMA3C-319aa and the GPX4 inhibitor RSL3 was more effective than monotherapy in vivo. Taken together, our findings reveal a novel NLS-dependent nuclear translocation mechanism mediated by SEMA3C-319aa and identify a new ferroptosis pathway in GC. SEMA3C-319aa may offer a promising adjuvant therapeutic strategy for GC.