Ferredoxin 1

Overview

Ferredoxin 1 (FDX1) is a mitochondrial iron-sulfur protein that has attracted substantial attention in biomedical research because of its role in copper-dependent cell death, known as cuproptosis. In this context, FDX1 is widely regarded as a key upstream regulator of copper toxicity in cells, particularly through its association with mitochondrial metabolism and lipoylated protein handling. Its expression has therefore been studied not only as a mechanistic component of cuproptosis, but also as a potential biomarker and therapeutic target in cancer and other copper-related disease settings.

Biologically, FDX1 is linked to mitochondrial function and metabolic stress responses. Recent studies have used it to probe how copper ions, copper ionophores, and copper-based nanomaterials can trigger mitochondrial collapse, alter lipoylated proteins such as DLAT, and induce cell death in tumor cells. In parallel, FDX1 has been investigated as a prognostic marker in gastric cancer and as a factor that may influence sensitivity to androgen receptor-Targeted therapies in prostate cancer.

Focus of Latest Publications

Recent publications have positioned FDX1 as a central mediator of copper-induced cytotoxicity and a candidate target for cancer therapy. In a study of GE11/RGD dual-ligand copper nanoassemblies for cervical cancer ablation, the rapid release of Cu2+ was reported to promote dihydrolipoamide S-acetyltransferase oligomerization, downregulate ferredoxin 1, and cause mitochondrial collapse, thereby initiating cuproptosis. This work linked FDX1 to a nanomedicine strategy designed to synchronize cuproptosis with photothermal therapy in recurrent cervical cancer models.

In gastric cancer, FDX1 was evaluated as a predictive biomarker and therapeutic target for lymph node metastasis. Using data-driven analyses, including The Cancer Genome Atlas and Gene Expression Omnibus resources, the study identified FDX1, LIAS, DLAT, MTF1, and GLS as key determinants of overall survival in patients with gastric cancer liver metastasis. FDX1 emerged as a potential independent prognostic factor, suggesting that altered cuproptosis-related biology may be clinically relevant in metastatic disease.

In prostate cancer, AR-Targeted therapies were reported to sensitize tumors to cuproptosis by transcriptionally activating FDX1. This finding connected androgen receptor signaling to copper-dependent lethality and suggested that AR antagonists may increase vulnerability to copper-induced cell death by elevating FDX1 expression. The study supports a mechanistic link between hormone-directed therapy and metabolic cell death pathways.

Additional studies reinforced the importance of FDX1 in copper-mediated cytotoxicity. In hepatocellular carcinoma models, knockout of ferredoxin 1 in Huh-7 cells reduced the cytotoxic effects of fucoidan-copper nanoparticles, underscoring the protein’s critical role in copper-induced cell death. In lung cancer research, paeoniflorin-copper-coordinated nanoparticles were shown to induce endoplasmic reticulum stress and downregulate FDX1 and DLAT, consistent with disruption of the cuproptosis-associated mitochondrial program. In a neuroprotection study, inhibition of cuproptosis by C-phycocyanin restored mitochondrial membrane potential, reduced oxidative stress, and normalized key cuproptosis markers including FDX1 and lipoylated DLAT in the setting of copper-induced mitochondrial damage and cognitive impairment.

Taken together, these studies place FDX1 at the intersection of mitochondrial metabolism, copper homeostasis, and regulated cell death. Across cancer and neurobiological models, changes in FDX1 expression or function were associated with altered sensitivity to copper, supporting its use as both a mechanistic marker and a possible therapeutic target.