Lung cancer, a prevalent malignancy, stands as the foremost cause of cancer-related fatalities worldwide. In 2023, it ranked second in morbidity and first in mortality among all cancers, with approximately 238,340 (12.1 %) new cases and 127,070 (20.8 %) deaths [1]. Non-small-cell lung cancer (NSCLC), constituting 85 % of lung cancers, primarily manifests as lung adenocarcinoma (LUAD) [2]. Despite advancements in surgical, radiotherapeutic, chemotherapeutic, targeted therapy, and immunotherapeutic approaches, LUAD patients continue to face high mortality rates due to treatment resistance and tumor recurrence [3], [4]. Consequently, investigating the molecular mechanisms driving LUAD progression and identifying novel therapeutic targets remains crucial.

SFXN1, initially identified as the gene mutated in a mouse mutant with anemia and axial skeletal abnormalities, was originally reported to be related to iron metabolism [5]. Cytoplasmic Fe2+ triggers SFXN1 expression on the mitochondrial membrane, facilitating Fe2+ translocation into mitochondria, enhancing ROS production, and inducing ferroptosis in sepsis-induced liver and acute lung injury [6], [7]. In 2018, SFXN1 was identified as a mitochondrial serine transporter in one-carbon metabolism, contributing to NADPH generation in proliferating cells [8]. SFXN1 has recently emerged as a potential oncogene, with mounting evidence supporting its overexpression and association with poor prognosis in various cancers, including LUAD [9], [10], [11]. Chen et al. and Zhang et al. independently reported an upregulation of SFXN1 in LUAD, which correlates with increased proliferation, metastasis, and poor prognosis [9], [11]. Recently, Liu et al. elucidated SFXN1 is involvement in regulating immune cell infiltration in LUAD through in silico analysis [10]. While these findings highlight the potential significance of SFXN1 in LUAD development, the underlying molecular mechanisms remain elusive.

In this study, we employed a comprehensive approach that included in silico, in vitro, and in vivo investigations to elucidate the underlying mechanisms of SFXN1 in LUAD progression. Targeted knockdown of SFXN1 was utilized to assess its potential as a therapeutic target. Our findings demonstrated that SFXN1 knockdown suppresses LUAD cell proliferation and migration in vitro, concomitant with disruptions in cell cycle, epithelial-mesenchymal transition (EMT), and ERK signaling. Furthermore, our analysis indicated that SFXN1 knockdown leads to reduced CCL20 expression and decreased infiltration of Foxp3+Tregs in vivo. These results suggest that targeting SFXN1 may represent a promising therapeutic strategy for LUAD.