# Glutathione metabolism–associated resistance to cisplatin and 5-FU in esophageal cancer: a paired transcriptomic study

## TL;DR

This study finds that resistance to a common chemotherapy in esophageal cancer is often present before treatment, with glutathione metabolism playing a key role.

## Contribution

The study identifies pre-existing glutathione metabolism features as a novel resistance mechanism in esophageal cancer chemotherapy.

## Key findings

- Recurrent tumors showed limited transcriptional changes after chemotherapy, with glutathione metabolism as a key resistance pathway.
- Genes like GSTP1 and GPX2 were highly expressed in recurrent tumors before and after treatment, indicating pre-existing resistance.
- Pretreatment molecular profiling could help guide therapy and improve outcomes in esophageal cancer patients.

## Abstract

Cisplatin plus 5-fluorouracil (CF) remains a cornerstone of treatment for locally-advanced esophageal cancer (EC). However, resistance to CF-based neoadjuvant chemotherapy (NAC) remains a major clinical challenge. Clarifying whether resistance-associated molecular features are induced by treatment or already present before therapy is crucial for improving patient stratification.

RNA sequencing was performed on paired tumor specimens from patients with EC treated with CF-based NAC, including pre-treatment biopsies (PreNAC) and post-treatment surgical samples (PostNAC) (n = 15; recurrence, n = 7; non-recurrence, n = 8). Differential gene expression analysis was conducted across four groups defined by sample timing (Pre vs. PostNAC) and recurrence status.

PostNAC transcriptional changes in recurrent tumors were relatively limited, with only 53 genes upregulated and 54 genes downregulated compared with PreNAC samples. Notably, genes involved in glutathione metabolism emerged as the dominant resistance-associated pathway and were consistently enriched in recurrent tumors at both PreNAC and PostNAC stages. Key glutathione-related genes, including GSTP1 and GPX2, were highly expressed in recurrent cases, indicating that major resistance-associated molecular features are often already established prior to chemotherapy rather than being newly acquired during NAC.

Our findings suggest that the molecular characteristics associated with CF resistance are frequently present before the initiation of chemotherapy. These results highlight the clinical potential of pretreatment molecular profiling as a strategy to guide therapeutic decision-making and optimize CF-based NAC in EC.

The online version contains supplementary material available at 10.1186/s12876-026-04664-1.