Free radical biology & medicine · 2026
The joint anti-hepatocellular carcinoma mechanism of selenium and lenvatinib mediated by Nrf2-ferroptosis axis in M2 tumor associated macrophage.
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Zhao Ying, Wang Yu, Zhao Wenzhi, Chen Li, Chen Huimin, Song Yajing, Tang Yuhan, Li Hongxia, Yao Ping
Аннотация
BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with limited treatment options. Lenvatinib demonstrates efficacy but is associated with significant toxicity at standard doses. Tumor-associated macrophages (TAMs), especially the pro-tumor M2 phenotype, contribute to an immunosuppressive microenvironment in HCC by promoting immune evasion. Selenium (Se), an essential trace element with anticancer properties, can reduce M2-TAM infiltration; however, its potential synergy with low-dose lenvatinib (L-Len) to enhance antitumor efficacy while minimizing toxicity remains unexplored.
METHODS: Subcutaneous HCC models were established to assess the therapeutic effects of Se combined with L-Len. Tumor growth, toxicity, and infiltration of M2-TAMs were evaluated. Mechanistic studies analyzed Nrf2 activation and downstream targets (GPx4/xCT) in TAMs to determine ferroptosis-inducing effects of combined treatment.
RESULTS: Se + L-Len showed comparable antitumor efficacy to standard-dose lenvatinib but with reduced toxicity. The combination reduced M2-TAMs infiltration and induced ferroptosis by suppressing Nrf2 and GPx4/xCT.
CONCLUSION: Se enhances L-Len's efficacy, and a key mechanism contributing to this synergy appears to be the targeting of Nrf2-mediated ferroptosis in M2-TAMs. This suggests a potential strategy to improve HCC treatment while minimizing toxicity, which warrants further investigation in more clinically relevant models.
METHODS: Subcutaneous HCC models were established to assess the therapeutic effects of Se combined with L-Len. Tumor growth, toxicity, and infiltration of M2-TAMs were evaluated. Mechanistic studies analyzed Nrf2 activation and downstream targets (GPx4/xCT) in TAMs to determine ferroptosis-inducing effects of combined treatment.
RESULTS: Se + L-Len showed comparable antitumor efficacy to standard-dose lenvatinib but with reduced toxicity. The combination reduced M2-TAMs infiltration and induced ferroptosis by suppressing Nrf2 and GPx4/xCT.
CONCLUSION: Se enhances L-Len's efficacy, and a key mechanism contributing to this synergy appears to be the targeting of Nrf2-mediated ferroptosis in M2-TAMs. This suggests a potential strategy to improve HCC treatment while minimizing toxicity, which warrants further investigation in more clinically relevant models.