PSAT1 integrates ferroptosis resistance and immune evasion to drive hepatocellular carcinoma progression
- 1State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
- 2Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Abstract
The serine/glycine biosynthesis pathway plays a critical role in tumor progression and has emerged as a promising therapeutic target in cancer. Phosphoserine aminotransferase 1 (PSAT1) is a key enzyme in this pathway and has been implicated in the progression of multiple malignancies. However, the functional significance and underlying mechanisms of PSAT1 in hepatocellular carcinoma (HCC) remain largely undefined. In this study, we identify PSAT1 as a critical determinant of ferroptosis resistance in HCC. Elevated PSAT1 expression was positively associated with ferroptosis resistance and poor clinical outcomes in patients with HCC. Both in vitro and in vivo functional assays demonstrated that PSAT1 promotes HCC cell proliferation and suppresses ferroptosis through an HSPA5-mediated adaptive endoplasmic reticulum response. Mechanistically, PSAT1 interacts with and stabilizes BCLAF1, thereby enhancing HSPA5 messenger RNA stability and translation in HCC cells. In addition, PSAT1 remodels the tumor immune microenvironment by promoting M2 tumor-associated macrophage polarization and regulatory T cell infiltration. PSAT1 up-regulates NRF2 expression, which directly binds to the CCL5 promoter to enhance CCL5 production and secretion by tumor cells, thereby fostering an immunosuppressive microenvironment. Therapeutically, pharmacological inhibition of PSAT1 with aminooxyacetic acid markedly potentiated the antitumor efficacy of anti-PD-1 immunotherapy. Our study reveals a previously unrecognized role of PSAT1 in coordinating ferroptosis resistance and immune escape in HCC and highlights therapeutic targeting of PSAT1 as a promising strategy for HCC treatment.
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BibTeX
@article{zhang2026psat1,
title = {{PSAT1 integrates ferroptosis resistance and immune evasion to drive hepatocellular carcinoma progression}},
author = {Chi Zhang and Yue Yang and Wei Tian and Jia Zhang and Chao Ge and Lili Meng and Yuqi Liu and Zhujun Wei and Hua Tian},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aei7877},
url = {https://www.science.org/doi/abs/10.1126/sciadv.aei7877},
note = {CC BY},
}
RIS
TY - JOUR
TI - PSAT1 integrates ferroptosis resistance and immune evasion to drive hepatocellular carcinoma progression
AU - Chi Zhang
AU - Yue Yang
AU - Wei Tian
AU - Jia Zhang
AU - Chao Ge
AU - Lili Meng
AU - Yuqi Liu
AU - Zhujun Wei
AU - Hua Tian
PY - 2026
DA - 2026/10/28
JO - Science Advances
DO - 10.1126/sciadv.aei7877
UR - https://www.science.org/doi/abs/10.1126/sciadv.aei7877
AB - The serine/glycine biosynthesis pathway plays a critical role in tumor progression and has emerged as a promising therapeutic target in cancer. Phosphoserine aminotransferase 1 (PSAT1) is a key enzyme in this pathway and has been implicated in the progression of multiple malignancies. However, the functional significance and underlying mechanisms of PSAT1 in hepatocellular carcinoma (HCC) remain largely undefined. In this study, we identify PSAT1 as a critical determinant of ferroptosis resistance in HCC. Elevated PSAT1 expression was positively associated with ferroptosis resistance and poor clinical outcomes in patients with HCC. Both in vitro and in vivo functional assays demonstrated that PSAT1 promotes HCC cell proliferation and suppresses ferroptosis through an HSPA5-mediated adaptive endoplasmic reticulum response. Mechanistically, PSAT1 interacts with and stabilizes BCLAF1, thereby enhancing HSPA5 messenger RNA stability and translation in HCC cells. In addition, PSAT1 remodels the tumor immune microenvironment by promoting M2 tumor-associated macrophage polarization and regulatory T cell infiltration. PSAT1 up-regulates NRF2 expression, which directly binds to the CCL5 promoter to enhance CCL5 production and secretion by tumor cells, thereby fostering an immunosuppressive microenvironment. Therapeutically, pharmacological inhibition of PSAT1 with aminooxyacetic acid markedly potentiated the antitumor efficacy of anti-PD-1 immunotherapy. Our study reveals a previously unrecognized role of PSAT1 in coordinating ferroptosis resistance and immune escape in HCC and highlights therapeutic targeting of PSAT1 as a promising strategy for HCC treatment.
SN - 2375-2548
ER -