文章：

NRF2-SOX4复合物调控肝细胞癌中PSPH的表达并调节M2型巨噬细胞分化

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

原文发布日期：2025-08-25 

英文摘要：

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.

摘要翻译：

体解离所肝细胞癌（HCC）的进展与代谢重编程和免疫逃逸密切相关。然而，驱动这些过程的转录调控网络仍未明确。本研究通过免疫共沉淀和邻近连接实验证实，转录因子SOX4与NRF2形成应激响应复合体。该过程由p62介导的KEAP1-SOX4复合调控。荧光素酶报告基因和染色质免疫沉淀实验表明，SOX4-NRF2复合体直接激活磷酸丝氨酸磷酸酶（PSPH）的转录，从而增强丝氨酸生物合成及其下游代谢物产生，这些代谢物对氧化磷酸化（OXPHOS）和氧化还原平衡至关重要。抑制SOX4或NRF2会降低PSPH表达，加剧氧化损伤（以4-羟基壬烯醛升高为标志），并增强HCC细胞对索拉非尼治疗的敏感性。此外，PSPH驱动的代谢物（尤其是丝氨酸）促进M2样巨噬细胞极化，可能助长免疫抑制性肿瘤微环境。对TCGA及临床队列中HCC样本的分析证实，SOX4/NRF2/PSPH高表达与M2巨噬细胞浸润增加及患者不良预后相关。我们的研究揭示了一个前所未有的SOX4-NRF2-PSPH调控环路，该环路将癌症代谢与免疫调节相耦合。靶向这一轴心可能为同时破坏HCC的代谢支持和免疫逃逸提供潜在治疗策略。

原文链接：

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