UBE2S promotes small cell lung cancer transformation and progression via monitoring metabolic remodeling and cell cycle

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy characterized by rapid progression and poor survival. While the ubiquitin-conjugating enzyme E2 S (UBE2S) has been investigated in non-small cell lung cancer (NSCLC), its expression, functional roles, and underlying mechanisms in SCLC remain largely undefined. This study aims to elucidate the contribution of UBE2S to SCLC pathogenesis, metabolic reprogramming, and cellular plasticity. UBE2S expression was analyzed using public databases (TCGA, GEO, LinkedOmics, TIMER, UALCAN, etc.) and validated by immunohistochemistry on lung cancer tissue microarrays. Gain- and loss-of-function experiments were conducted in SCLC cell lines. Multi-omics approaches—including single-cell RNA sequencing (scRNA-seq), proteomics, metabolomics, and immunoprecipitation-mass spectrometry (IP-MS)—were employed. Virtual screening was performed against the UBE2S structure to identify potential inhibitors. Statistical significance was assessed using Student’s t-test, ANOVA or adjusted p-values as appropriate. UBE2S was significantly upregulated in SCLC compared to NSCLC, with protein levels escalating from lung squamous cell carcinoma (LUSC) to lung adenocarcinoma (LUAD) to SCLC. Elevated UBE2S expression correlated with advanced stage in both LUAD and SCLC. Functional studies in vitro and in vivo demonstrated that UBE2S promotes SCLC proliferation and cell cycle progression by driving G1/S transition. ScRNA-seq revealed specific enrichment of UBE2S in SCLC cells and implicated it in NSCLC-to-SCLC phenotypic plasticity. Integrated proteomic and metabolomic analyses indicated that UBE2S remodels metabolism, activating pathways such as folate and amino acid biosynthesis. IP-MS identified the transcription factor DLX6 as a novel UBE2S interactor, with UBE2S overexpression reducing DLX6 protein stability. Virtual screening integrated with functional assays identified Odetiglucan as a selective proliferation inhibitor for UBE2S-high cells. UBE2S drives SCLC malignant progression by regulating cell cycle and metabolic reprogramming, mediated in part through its interaction with DLX6. Odetiglucan, with its documented immunomodulatory functions, represents a promising therapeutic candidate for SCLC with high UBE2S expression. Our findings establish UBE2S as a key oncoprotein and potential therapeutic target in SCLC.