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

Oncogene volume 44, pages 3679–3693 (2025)Cite this article

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Abstract

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.

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Fig. 1: CircSEMA3C RNA expression levels are suppressed in GC.
Fig. 2: The novel peptide SEMA3C-319aa, encoded by circSEMA3C, reduces GC cell viability.
Fig. 3: GSH metabolism-mediated ferroptosis by LDHA is essential for SEMA3C-319aa- induced GC cell death.
Fig. 4: SEMA3C-319aa binding to LDHA promotes the degradation of GPX4 via K48-linked ubiquitination in GC.
Fig. 5: SEMA3C-319aa enhances the translocation of LDHA to the nucleus, where it gains a moonlighting function in GC.
Fig. 6: SEMA3C-319aa NLS enhances the sensitivity of ferroptosis in GC via the nuclear LDHA.
Fig. 7: Treatment with SEMA3C-319aa combined with RSL3 inhibits GC tumor growth in vivo.

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Data availability

Data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

HFE145 immortalized gastric epithelial cells were supported by Dr Hassan Ashktorab and Dr Duane Smoot. The authors would also like to thank Prof. Jessica Tamanini for language editing this manuscript.

Funding

This work was supported in part by the National Natural Science Foundation of China (grant nos. 82173290, 82172946, 82273029), the Natural Science Foundation of Guangdong province (grant no. 2022A1515010706), the Shenzhen Science and Technology Program (grant no. JCYJ20230808105319039, JCYJ20240813142004006, JCYJ20240813143100001), Shenzhen Medical Research Fund (grant no. A2301014) and the Medicine Plus Program of Shenzhen University (grant no. 2024YG016).

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  1. These authors contributed equally: Siyu Xiao, Yin Peng.

Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of Genome Stability and Disease Prevention, Department of Pathology, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, People’s Republic of China

    Siyu Xiao, Yin Peng, Lehua Peng, Xiaoya Xie, Jiequan Qin, Huizhen Ma, Xinyi Kang, Chuhan Bing, Bingyan Huang, Ke Liang, Yidan Zhao, Xueying Rong, Xianling Feng, Xinmin Fan, Zhe Jin & Xiaojing Zhang

  2. Department of Otorhinolaryngology-Head and Neck Surgery, South China Hospital, Medical School, Shenzhen University, Shenzhen, China

    Siyu Xiao

  3. Department of Medicine and Cancer Center, Howard University, College of Medicine, Washington, DC, USA

    Hassan Ashktorab

  4. Department of Pathology, Shenyang Medical College, Shenyang, Liaoning, People’s Republic of China

    Zhong Zhang

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Contributions

SYX and YP conceptualized the study. SYX, LHP, XYX, JQQ, HZM, XYK, CHB, KL, YDZ, and XYR conducted the experiments. BYH and XLF collected GC samples from patients, and performed the sequencing data analysis. HA supplied the HFE-145 cell line. SYX, YP, XMF, and ZZ wrote and editor the manuscript. XJZ and ZJ contributed to the conception of the study, wrote, reviewed and edited the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Zhe Jin or Xiaojing Zhang.

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The authors declare no competing interests.

Ethical approval and consent to participate

All human tissues were collected from the Department of General Surgery at the 1st Affiliated Hospital of Shenzhen University, with written informed consent provided. The study was approved by the Clinical Research Ethics Committee. All the research was performed in accordance with government policies and the Helsinki declaration. All experimental protocols concerning the handling of mice were approved by the Institutional Animal Care and Use Committee of Shenzhen University (No. PN-202300134).

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Xiao, S., Peng, Y., Peng, L. et al. The novel protein SEMA3C-319aa triggers glutathione metabolism-dependent ferroptosis in gastric cancer. Oncogene 44, 3679–3693 (2025). https://doi.org/10.1038/s41388-025-03542-6

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