Work

DENR reduces cisplatin sensitivity in esophageal squamous cell carcinoma via ATF4-Mediated ferroptosis inhibition

Year: 2025

Type: article

Abstract: Cisplatin (DDP)-based chemotherapy is a cornerstone in the treatment of esophageal squamous cell carcinoma (ESCC), yet resistance to DDP remains a major clinical obstacle. Ferroptosis, an iron-dependent form of regulated cell death, has been implicated in tumor sensitivity to chemotherapy. However, the molecular mechanisms governing ferroptosis in ESCC remain incompletely understood. This study aimed to investigate the role of density-regulated re-initiation and release factor (DENR) in regulating cisplatin sensitivity in ESCC, with a particular focus on its involvement in ferroptosis through activating transcription factor 4 (ATF4). DENR was significantly upregulated in ESCC and associated with poor prognosis. DENR overexpression reduced the sensitivity of ESCC cells to DDP and suppressed ferroptosis, as evidenced by decreased ROS accumulation, Fe 2+ levels, and ferroptosis marker expression. Conversely, DENR knockdown enhanced ferroptosis and DDP-induced cytotoxicity. Mechanistically, DENR promoted ATF4 expression, and silencing ATF4 partially reversed the ferroptosis-inhibitory and DDP resistance effects mediated by DENR. In vivo, DENR overexpression enhanced tumor growth and diminished DDP efficacy, which was mitigated by ATF4 knockdown. DENR promotes cisplatin resistance in ESCC by inhibiting ferroptosis through an ATF4-dependent mechanism. Targeting the DENR/ATF4 axis may represent a promising strategy to overcome chemoresistance in ESCC. • Identification of DENR as a novel modulator of cisplatin resistance in esophageal squamous cell carcinoma (ESCC). • Mechanistic insight : DENR enhances ATF4 expression to inhibit ferroptosis, a regulated form of cell death. • In vitro and in vivo findings demonstrate DENR's role in chemoresistance. • Potential therapeutic implications of targeting the DENR/ATF4 axis to overcome drug resistance.

Source: Biochemical and Biophysical Research Communications

DOI: 10.1016/j.bbrc.2025.152839

Authors: Lu Hou, Xiaoqing Ge, Chong Zhao, Chen Yang, Xianen Fa

Institutions: Second Affiliated Hospital of Zhengzhou University, Zhengzhou University

Language: English

Topic: Ferroptosis and cancer prognosis

Subfield: Pulmonary and Respiratory Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,110