Esophageal cancer (EC) is driven by complex dysregulated molecular networks, and ferroptosis—an iron‐dependent, non‐apoptotic form of regulated cell death—has emerged as a critical modulator of tumorigenesis. However, the functional contribution and mechanistic basis of GPR176 in ferroptosis regulation during EC progression remain largely unexplored. Here, we integrated computational and experimental approaches to delineate the role of GPR176 and its upstream regulator E2F4 in EC ferroptosis. Bioinformatic analysis revealed consistent upregulation of both GPR176 and E2F4 in EC tissues, which was further confirmed by molecular validation. Functional assays demonstrated that GPR176 overexpression conferred resistance to ferroptosis in EC cells, as reflected by reduced malondialdehyde, intracellular Fe 2+ , and lipid reactive oxygen species (ROS) accumulation, alongside altered expression of core ferroptosis mediators. This protective effect was associated with the suppression of mitophagy, as indicated by alterations in mitochondrial function and autophagy‐related markers. Mechanistically, we demonstrated that E2F4 directly binds to the GPR176 promoter and transcriptionally activates its expression. Rescue experiments further validated that GPR176 overexpression abrogated the enhanced mitophagy and ferroptosis induced by E2F4 depletion. Collectively, our findings define an E2F4/GPR176/mitophagy axis that acts to suppress ferroptosis in EC, highlighting this pathway as a novel therapeutic target for inducing ferroptosis in EC intervention.
Xu et al. (Thu,) studied this question.