Fig 2: The heterogeneity of ESCC tumor microenvironment and targeted gene distributions.A Single-cell-level cell types of ESCC obtained via UMAP and t-SNE analysis. B Proportion of cell types. C Cell communication among the 9 cell types, D Metabolic pathways in the 9 cell types. E Distribution of IL22RA1 and FAM221A at ESCC single-cell level.

Fig 3: Integrative AI-driven network analysis nominates AZD7762 as a multitarget repurposed agent for ESCC.A Radial protein–protein interaction network of IL22RA1, FAM221A and the other prognostic genes (GUF1, TCF19, SLC35F5, PRKAB1, IQCB1) with cell-cycle, DNA-repair and EMT-related interactors. B Multilayer network connecting AZD7762 to the seven core genes and their enriched hallmark programmes, including DNA repair, G2M checkpoint, E2F targets, apical junction, EMT, inflammatory response and IL-6/JAK–STAT signaling. C Drug–target network comparing AZD7762 with other candidate compounds (Roscovitine, Palbociclib, Olaparib, MK-8776, VX-970, Cisplatin, Gemcitabine, 5-FU, Paclitaxel, Etoposide), showing that AZD7762 has the most extensive coverage across IL22RA1, FAM221A and extended checkpoint/cell-cycle targets (CHEK1, CHEK2, CDK1, CCNB1). D Large integrative systems network summarizing AZD7762-centered connections among gene targets, hallmark pathways, ESCC molecular/risk subgroups, cell states and other drugs, providing an overview of the AI-driven multitarget repurposing landscape in ESCC.

Fig 4: Structural and mechanistic view of AZD7762 as a multitarget inhibitor in esophageal squamous cell carcinoma (ESCC).A Chemical structure of the checkpoint kinase inhibitor AZD7762. B, C Predicted binding modes of AZD7762 in the IL22RA1 and FAM221A binding pockets. D Two-dimensional interaction diagrams showing key contacts between AZD7762 and residues in IL22RA1 and FAM221A. E Schematic model illustrating how AZD7762 inhibits IL22RA1-driven JAK–STAT signaling and FAM221A-related cell-cycle/DNA-repair pathways, reducing proliferation and migration/invasion while increasing apoptosis/DNA damage in ESCC cells.

Fig 5: Durg repurposing strategy design for ESCC patients.A Drug sensitivity analysis. B ADMET-AI analysis. C Molecular docking analysis of FAM221A and AZD7762. D Molecular docking analysis of IL22RA1 and AZD7762.