The incidence of esophageal squamous cell carcinoma (ESCC) is high and the prognosis is poor. It has become one of the important factors threatening the economic development and social stability of the region. The lack of effective early diagnostic biological indicators is the main reason for the late visit time and high mortality rate of clinical patients with ESCC. This study aims to investigate the role of long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) in predicting the prognosis and survival of patients with ESCC.Prognosis-related genes were studied by analyzing RNA sequencing data of ESCC in The Cancer Genome Atlas (TCGA) database, and they were divided into a training cohort (n=83) and a test cohort (n=76). A risk score model was constructed and prognosis-related markers were verified.Nine prognosis-related genes (RP11-51F16.1, FABP3, RP11-4K3-A.3, GNG12-AS1, RP11-2N1.2, PRICKLE2-AS1, KB-1254G8.1, AC132825.1, and RP11-294N21.3) were screened out. Further construction of the risk score model revealed that the risk score was an independent prognostic factor. In addition, this study integrated prognostic markers and combined clinical features to develop a nomogram for predicting the overall survival (OS) rate for 1 to 3 years. Through quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) staining experiments, this study found that FABP3 was upregulated in ESCC, and patients with high expression of FABP3 had a shorter OS (P=0.04), and the upregulation of FABP3 was significantly correlated with the degree of differentiation of ESCC (P=0.04). Gene Set Enrichment Analysis (GSEA) indicated that the functions related to metabolism were mainly concentrated in the high-risk group. From a metabolic perspective, they played a role in regulating the tumorigenesis process. The analysis of changes in chemotherapy drug resistance found that the half maximal inhibitory concentration (IC50) of 25 drugs was higher in the high-risk group, which confirmed that this feature played an important role in the prognosis and treatment of ESCC.This study identified a new set of characteristics of nine prognostic genes related to ESCC, which may provide ideas for prognosis prediction and new therapeutic methods for ESCC patients.Copyright © 2025 AME Publishing Company. All rights reserved.