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NRF2-SOX4 complex regulates PSPH in hepatocellular carcinoma and modulates M2 macrophage differentiation

Cancer Gene Therapy (2025)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) progression is tightly linked to metabolic reprogramming and immune evasion. However, the transcriptional networks driving these processes remain misunderstood. Here, we identified a novel regulatory axis wherein the transcription factor SOX4 formed a stress-responsive complex with NRF2, as confirmed by co-immunoprecipitation and proximity ligation assay. This process was orchestrated via p62-mediated disruption of the KEAP1–SOX4 complex. The SOX4–NRF2 complex directly activated Phosphoserine Phosphatase (PSPH) transcription—as revealed by luciferase reporter and chromatin immunoprecipitation—enhancing serine biosynthesis and downstream metabolites critical for oxidative phosphorylation (OXPHOS) and redox balance. Inhibition of SOX4 or NRF2 impaired PSPH expression, exacerbated oxidative damage—marked by elevated 4-hydroxynonenal—and increased sensitivity to sorafenib treatment in HCC cells. Furthermore, PSPH-driven metabolites, particularly serine, fostered M2-like macrophage polarization, thereby potentially contributing to the promotion of an immunosuppressive tumor microenvironment. Analysis of HCC specimens from TCGA and clinical cohorts confirmed that high SOX4/NRF2/PSPH expression was correlated with increasing M2 macrophage infiltration and poor patient prognosis. Our findings revealed a previously unrecognized SOX4–NRF2–PSPH regulatory loop that coupled cancer metabolism with immune modulation. Targeting this axis may offer a promising therapeutic avenue to simultaneously disrupt metabolic support and immune evasion in HCC.

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Fig. 1: SOX4 was regulated via the KEAP1/p62 pathway.
Fig. 2: NRF2 formed a complex with SOX4.
Fig. 3: SOX4 was crucial for the nuclear translocation of NRF2 and its downstream genes.
Fig. 4: NRF2/SOX4 complex regulated the PSPH promoter.
Fig. 5: PSPH expression was elevated, associated with poor prognosis, and correlated with expression of SOX4, NRF2 in patients with HCC.
Fig. 6: Metabolite profiles in Hep3B and Hep3B SOX4−/− cells versus clinical specimens.
Fig. 7: NRF2/SOX4 modulated the polarization of M2 macrophage, enhanced by environmental serine in a THP1 cell model.

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Data availability

The authors declare that all of the data mentioned in this paper are available in the manuscript itself or in the supplementary results.

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Acknowledgements

The authors are grateful for the valuable assistance received from the Microscopy and Core laboratory, Research Specimen Processing Laboratory of Chang Gung Memorial Hospital. We are also grateful to our colleagues at the Health Aging Research Center in Chang-Gung University, Taiwan. In addition, we would like to thank Miss Yi-Ping Liu for assisting in clinical data retrieval/processing.

Funding

Financial support was provided by the Chang Gung Medical Foundation in Taiwan (CMRPG3N0451/2 for CLT; CMRPVVM0091 for MCY; CMRPD1K0711 for CNT) and the National Science and Technology Council of Taiwan (111-2320-B-182-034, 112-2320-B-182-013 to CNT; 111-2314-B-182A-035-MY3 for CLT).

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Author notes

  1. These authors contributed equally: Chi-Neu Tsai, Ming-Chin Yu.

Authors and Affiliations

  1. Graduate Institute of Clinical Medical Science, Chang-Gung University, Taoyuan City, Taiwan

    Chi-Neu Tsai, Kuan-Chuan Feng & Tien-An Lin

  2. Department of Surgery, New Taipei Municipal TuCheng Hospital, Operated by Chang-Gung Medical Foundation, New Taipei City, Taiwan

    Chi-Neu Tsai, Ming-Chin Yu, Chun-Hsing Wu, Song-Fong Huang & Tien-An Lin

  3. College of Medicine, Chang Gung University, Taoyuan City, Taiwan

    Ming-Chin Yu & Song-Fong Huang

  4. Department of Biotechnology, Ming-Chuan University, Taoyuan City, Taiwan

    Yun-Shien Lee

  5. Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan City, Taiwan

    Yi-Chin Li

  6. Department of Biomedical Sciences, Chang-Gung University, Taoyuan City, Taiwan

    Mei-Ling Cheng

  7. Department of Anatomical Pathology, Taipei Institute of Pathology, Taipei City, Taiwan

    Sey-En Lin

  8. Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Taoyuan City, Taiwan

    Chia-Lung Tsai

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Contributions

CL Tsai, MC Yu, and CN Tsai conceptualized and wrote the manuscript; YS Lee statistically analyzed the TCGA-LIHC data; KC Feng and CH Wu performed the western blotting, transfection, and cell culture experiments; SE Lin, SF Huang, and TA Lin helped in the analysis of clinical specimen collections; ML Cheng and YC Li helped in the metabolites analyses.

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Correspondence to Chia-Lung Tsai.

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This study was approved by the Institutional Review Board of Chang Gung Memorial Hospital (approval number: 202202182B0). All methods were performed in accordance with relevant guidelines and regulations, including the Declaration of Helsinki. Written informed consent was obtained from all participants prior to their inclusion in the study. No identifiable images or other personal details of participants are included in this manuscript; therefore, specific consent for publication was not required.

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Tsai, CN., Yu, MC., Lee, YS. et al. NRF2-SOX4 complex regulates PSPH in hepatocellular carcinoma and modulates M2 macrophage differentiation. Cancer Gene Ther (2025). https://doi.org/10.1038/s41417-025-00951-3

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