Exploratory identification of lycorine as a potential inhibitor of the ACP2/YME1L1 prognostic axis in esophageal squamous cell carcinoma: a multi-omics and computational hypothesis.

Esophageal squamous cell carcinoma (ESCC) continues to pose significant therapeutic challenges due to its aggressive behavior and suboptimal outcomes. The mitochondrial unfolded protein response (MUPR) pathway has emerged as a potential contributor to tumor progression, yet its role in ESCC prognosis and therapy remains insufficiently characterized. This study therefore seeks to systematically identify MUPR-associated prognostic genes in ESCC and to evaluate their potential as targets for therapeutic intervention. This study analyzed public databases to correlate MUPR pathway genes with ESCC prognosis, identifying YME1L1 and ACP2. These genes were used to construct a prognostic risk model, and single-cell RNA sequencing (scRNA-seq) was employed to determine their cellular expression patterns. Furthermore, the expression levels of the identified genes were experimentally validated in human ESCC cell lines using Reverse Transcription-quantitative PCR (RT-qPCR). Subsequently, the potential of these genes as drug targets was assessed. Following computational screening, lycorine emerged as a promising candidate. Rather than relying solely on molecular docking, this study performed molecular dynamics (MD) simulations to assess the stability of the binding interactions over time. The prognostic model was able to stratify patients into high- and low-risk groups that showed significantly different survival outcomes. At the cellular level, YME1L1 and ACP2 exhibited pronounced activity in B cells and neutrophils. RT-qPCR analysis demonstrated a significant downregulation of YME1L1 and ACP2 in ESCC cell lines compared to normal esophageal epithelial cells (P < 0.05), demonstrating high concordance between our bioinformatics predictions and experimental evidence. The drug screening identified lycorine as a promising candidate, with a predicted binding energy of − 9.0 kcal/mol to ACP2. MD simulations demonstrated the stability of these interactions: both the ACP2-lycorine and YME1L1-lycorine complexes remained stable throughout the simulation period, maintaining their structural integrity and key hydrogen bonds. This study identified ACP2 and YME1L1 as a novel prognostic signature in ESCC, supported by preliminary transcriptional validation, and proposed the natural compound lycorine as a computational candidate for inhibiting this axis. Our work established a conceptual link between prognostic biomarkers and a candidate therapeutic, providing a computationally derived rationale for future experimental and translational studies in ESCC. Further investigations are warranted to validate lycorine’s efficacy in vivo and to explore its potential synergy with existing therapies, with the ultimate goal of improving clinical outcomes.