Txndc12, a thioredoxin domain-containing protein, is located in the endoplasmic reticulum. It plays a crucial role in regulating lipid peroxidation and ferroptosis, an iron-dependent cell death process mainly triggered by reactive oxygen species (ROS) and lipid peroxidation. It is also involved in the epithelial-mesenchymal transition (EMT) and metastasis in some cancers, and may be associated with the immune response and redox homeostasis [1-3, 6]. Genetic models such as gene knockout (KO) or conditional knockout (CKO) mouse models could potentially help in further understanding its functions.

In cancer cells, knockdown of Txndc12 promotes ferroptosis. In leukemia cells, its inducible expression during ferroptosis is inhibited by ATF4 knockdown. TXNDC12 overexpression restores the sensitivity of ATF4-knockdown cells to ferroptosis, and it acts in a GPX4-independent manner to inhibit lipid peroxidation [1]. In glioma cells, Txndc12 knockdown promotes erastin-induced increase in ROS, lipid peroxidation, and Fe2+ levels, and decreases glutathione content. TXNDC12 is involved in ferroptosis by regulating SLC7A11 [2]. In pancreatic cancer cells, knockdown of Txndc12 significantly inhibits cell proliferation, migration, and invasion, and promotes apoptosis. It inhibits ferroptosis through the GSH/GGT7 axis [3].

In conclusion, Txndc12 is a key regulator in the endoplasmic reticulum-based anti-ferroptosis pathway in cancer cells. Its knockdown promotes ferroptosis, which enhances the tumor-suppressive effects. The study of Txndc12 in KO/CKO mouse models has provided insights into its role in cancer-related ferroptosis, potentially offering new targets for cancer treatment [1-4].