The dynamic balance between iron metabolism and lipid metabolism is crucial for maintaining cellular energy supply. In rapidly proliferating tumor cells, iron not only serves as a core element for cellular respiration, DNA synthesis, and antioxidant reactions but also plays a key role in regulating metabolic signaling pathways. In recent years, fatty acid oxidation (FAO) has been recognized as a preferred energy source for certain tumor cells under specific conditions. However, how tumors coordinate iron homeostasis with lipid metabolic reprogramming to adapt to energy-deficient environments and promote growth remains an open question for further investigation.

Blocking TF-specific binding is key to inhibiting liver tumor cell growth

On January 31, 2025, Professor Daqian Xu from Zhejiang University published a research paper in PNAS (IF=9.4) titled "Transferrin promotes fatty acid oxidation and liver tumor growth through PHD2-mediated PPARα hydroxylation in an iron-dependent manner." This study unveiled a novel pro-carcinogenic mechanism of transferrin (TF) in hepatocellular carcinoma (HCC) cells. The research demonstrated that under glucose deprivation conditions, AMPK (AMP-activated protein kinase)-dependent phosphorylation of transferrin at S685 exposes its nuclear localization signal (NLS), facilitating its binding to importin α7 (IPOα7) and subsequent nuclear translocation. Once translocated into the nucleus, TF interacts with peroxisome proliferator-activated receptor alpha (PPARα), enhancing its stability and thereby promoting FAO.

Mechanism of Iron Metabolism in Regulating Tumor Development ¹

At the molecular level, transferrin promotes the FAO process and facilitates liver cancer cell growth by upregulating iron-dependent prolyl hydroxylase domain-containing protein 2 (PHD2)-mediated hydroxylation of PPARα at P87, which in turn inhibits Murine Double Minute 2 (MDM2)-mediated PPARα degradation. Reconstruction of TF S685A and NLS mutants or knock-in of the PPARα P87A mutation in mouse models effectively suppresses PPARα-mediated FAO, enhances hepatocellular carcinoma (HCC) cell apoptosis, and impedes liver cancer progression. Furthermore, blocking the specific peptide binding of TF pS685 can inhibit the AMPK–transferrin–PPARα axis. When combined with the classical AMPK activator metformin, this blockade synergistically suppresses tumor growth. This study not only reveals the critical role of TF in metabolic regulation in liver cancer but also provides a novel therapeutic target for HCC treatment.

Abnormal expression of TF/TFR is closely associated with the development of various malignant tumors

In the iron metabolism regulatory network, the abnormal expression of key proteins (such as TF and TFR) is closely associated with the development of liver cancer, lung cancer, pancreatic cancer, nasopharyngeal cancer, prostate cancer, breast cancer, ovarian cancer, colorectal cancer, brain tumors, and leukemia.

Expression of Transferrin-R in Various Tumors

Excessive TF can promote iron uptake in tumor cells and accelerate the clathrin-mediated endocytic cycle. The primary role of TF in tumor cells is to facilitate the absorption of iron ions, which are crucial for the production and metabolism of all cells, including tumor cells. Therefore, by binding antibodies to TFR, the absorption of iron ions in tumor cells can be blocked, leading to their death. TFR, known as the Trojan horse, can transport antibodies across the blood-brain barrier after binding to them, thereby enabling the treatment of tumors or diseases related to the nervous system. Additionally, recent research shows that TransTACs can drive the degradation of multiple membrane proteins, significantly improving the internalization efficiency of POI (protein of interest). TransTACs are bispecific antibodies targeting membrane target proteins and TfR1, guiding the POI into cells via the TFR1 on the cell surface, thereby initiating endolysosomal degradation. Studies have shown that over 80% of targets in different cells can be rapidly degraded.

High-Quality Tools Support Iron Metabolism Targeted Drug Development

To meet the development needs of iron metabolism-related tumor and neurodelivery drugs, ACROBiosystems has launched a series of high-quality tools that support applications from the molecular to the cellular level, including:

•  Recombinant Proteins: Transferrin R, Transferrin R2, Transferrin R2 alpha, Transferrin, Melanotransferrin. They are expressed in human-derived cells (HEK293) and validated by SDS-PAGE, SEC-MALS, ELISA, SPR, featuring high purity, high activity, high batch-to-batch consistency. They are suitable for applications in immunization, antibody screening, and candidate drug functional validation.

•  Stable Cell Line: Transferrin R, Transferrin. Transferrin R and Transferrin proteins are stably expressed on the surface of host cells and are suitable for long-term use. They support antibody drug activity screening (cell-level binding and blocking) and evaluation of CAR molecule cytotoxicity, providing essential tools for drug functional testing.

ACROBiosystems performs batch-by-batch quality control on all products, verifying properties such as purity and binding activity. Free protocols with detailed experimental parameters and procedures are provided to accelerate your R&D process.

References：

1.Transferrin promotes fatty acid oxidation and liver tumor growth through PHD2-mediated PPARα hydroxylation in an iron-dependent manner, Proc. Natl. Acad. Sci. U.S.A. 122 (5) e2412473122, https://doi.org/10.1073/pnas.2412473122 (2025).