ETHE1 Orchestrates Metabolic Reprogramming to Drive Lung Cancer Progression and Therapeutic Resistance

Background: Ethylmalonic encephalopathy 1 (ETHE1), a persulfide dioxygenase, is abnormally expressed in various malignancies, but its mechanism and therapeutic potential in lung cancer remain unclear. This study aimed to elucidate the molecular mechanisms through which ETHE1 promotes lung cancer progression via coordination of the PI3K/AKT signaling pathway and tumor metabolism. The feasibility of using ETHE1 as a therapeutic target was also explored. Methods: Bioinformatics analysis was used to assess ETHE1 expression levels in lung cancer tissues and its relationship with patient prognosis. ETHE1-overexpressing and ETHE1-silenced lung cancer cell models were constructed. CCK-8, BrdU, and Transwell assays were used to detect cell proliferation, migration, and invasion capabilities. Nude mouse lung metastasis models were established to validate the functions of ETHE1 in vivo. Western blotting was used to analyze the activation status of the PI3K/AKT signaling pathway. Coexpression analysis and functional enrichment analysis were performed to explore the mechanisms underlying the effects of ETHE1. Molecular docking and cellular experiments were employed to screen potential ETHE1 inhibitors and evaluate their antitumor effects. Results: ETHE1 was significantly overexpressed in human lung cancer tissues and closely associated with poor patient prognosis. Functional enrichment analysis revealed that genes coexpressed with ETHE1 were involved mainly in cellular metabolism and signal transduction processes. In vitro and in vivo experiments confirmed that ETHE1 overexpression significantly promoted lung cancer cell proliferation, migration, invasion, and lung metastasis. Mechanistic studies revealed that ETHE1 exerted oncogenic effects by activating the PI3K/AKT signaling pathway. ETHE1 forms a regulatory axis with the key metabolic enzyme hexokinase 2 (HK2), further amplifying its oncogenic effects. ETHE1 silencing significantly enhanced lung cancer cell sensitivity to chemotherapy drugs such as cisplatin and partially reversed drug resistance. Drug screening identified neobavaisoflavone (NBIF) as an effective ETHE1 inhibitor. NBIF treatment suppressed ETHE1 expression and enhanced chemotherapy sensitivity. Conclusion: ETHE1 plays a crucial role in lung cancer progression by activating the PI3K/AKT signaling pathway and regulating HK2-mediated metabolism. ETHE1 silencing or NBIF inhibition significantly suppressed malignant tumor behaviors and enhanced chemotherapy sensitivity. These findings establish ETHE1 as a promising therapeutic target for lung cancer treatment.