Selenomethionine suppresses lung tumor growth without hepatorenal toxicity in mice via the induction of apoptosis-ferroptosis and angiogenesis inhibition

The high global mortality rate of lung cancer underscores the urgent need for novel therapeutic strategies. Selenium (Se), an essential trace element, exhibits tumor-suppressive properties across malignancies. This study systematically evaluated the antitumor efficacy of selenomethionine (SeMet) compared with that of selenocysteine (SeCys) in Lewis lung carcinoma (LLC) cells in vitro and in tumor-bearing mice in vivo . Compared with SeCys (IC 50 = 45.89   μM), SeMet demonstrated superior cytotoxicity against LLC cells (IC 50 = 30.19   μM) and significantly inhibited proliferation and migration by inducing apoptosis and ferroptosis. In vivo , SeMet treatment inhibited tumour growth by 50.87% through the suppression of angiogenesis, outperforming SeCys (27.3%). Transcriptomic analysis revealed the downregulation of proangiogenic chemokines ( Cxcl1 , Cxcl2 , Cxcl3 , Cxcl5 ) and the upregulation of antitumor chemokines ( Cxcl9 , Cxcl16 ) in SeMet-treated tumors. Additionally, SeMet enhanced the activity of antioxidant enzymes (T-SOD and GSH-PX) and reduced the levels of proinflammatory cytokines (IL-6 and TNF-α) without hepatorenal toxicity. These findings establish SeMet as a multifaceted therapeutic candidate for lung cancer through dual induction of apoptosis-ferroptosis and angiogenesis inhibition.