Scientists studying a pig model of congenital hypothyroidism report that a shortage of thyroid hormone in the liver sets off ferroptosis, an iron-dependent form of cell death, through a newly described hormonal signaling pathway. The work, published as an open-access research article in Cellular & Molecular Biology Letters on 3 October 2026, was shared early as a peer-reviewed, accepted manuscript that may still undergo further edits before the final version of record appears.
Congenital hypothyroidism is described in the study as the most common endocrine disorder in neonates, with a reported worldwide incidence of roughly one in 1,400 to one in 2,800 births. The condition has previously been linked to liver injury, including hepatitis, metabolic dysfunction-associated steatotic liver disease and fibrosis, but the mechanisms behind that association have remained unclear. To investigate, the research team used a congenital hypothyroidism pig model they had generated previously, aiming to characterize hypothyroidism-induced liver injury and identify possible therapeutic targets.
The pigs spontaneously developed liver disease marked by hepatic inflammation and mild fibrosis. When the researchers performed RNA sequencing on liver samples, they found unexpected enrichment of the ferroptosis pathway in the hypothyroid animals. Further analysis supported that finding: the livers showed severe iron overload, impaired glutathione metabolism and excessive lipid peroxidation, the combination of biochemical changes that defines ferroptotic cell death.
A striking clinical parallel emerged from measurements in human patients. Both the congenital hypothyroidism piglets and human neonates with the condition showed marked elevations in serum iron, which the authors say suggests that iron dyshomeostasis is clinically significant in this disorder. Serum iron was examined in human congenital hypothyroidism neonates as part of the study’s integrated morphological, serological and multiomics characterization of the pig model.
At the molecular level, the team traced the damage to a loss of thyroid hormone signaling. Triiodothyronine, or T3, deficiency in the livers of the affected pigs impaired the AMPKα–GSK3β–NRF2–GPX4 antioxidant axis, a cascade that normally protects cells by keeping lipid peroxidation in check. GPX4, glutathione peroxidase 4, sits at the end of this pathway and is a well-known gatekeeper against ferroptosis.
Experiments in cultured hepatocytes pointed toward a protective role for the hormone itself. Treating cells with T3 effectively resisted ferroptosis induced by RSL3, a ferroptosis-inducing compound, in hepatic cell lines derived from humans, pigs and mice. The researchers also modulated the thyroid hormone receptor/retinoid X receptor pathway in these cells to clarify how T3 acts.
Mechanistically, the study concludes that T3 works through the THRβ/RXRβ heterodimer, a pair of nuclear receptors acting together, to transcriptionally upregulate PRKAA1, the gene encoding AMPKα1. Activated AMPKα1 then drives the GSK3β–NRF2–GPX4 signaling cascade, ultimately suppressing lipid peroxidation and ferroptosis. In hypothyroidism, the authors argue, the absence of T3 disrupts this THRβ/RXRβ–AMPKα1–GPX4 axis, leaving hepatocytes vulnerable to iron-driven cell death.
The authors frame their conclusions as establishing a relationship between the congenital hypothyroidism condition and iron dysregulation, and as identifying the T3–THRβ/RXRβ–AMPKα1–GPX4 pathway as an anti-ferroptotic axis whose impairment may contribute to hepatic ferroptosis and liver injury in the pig model. They suggest the findings offer new insight into the pathogenesis of hypothyroidism-induced liver injury and point to potential therapeutic targets for this condition and other ferroptosis-related liver diseases.
Several caveats matter for interpreting the results. The central mechanistic findings come from a pig model and from cell lines, and the human contribution is limited to serum iron measurements in affected neonates, which show an association rather than a demonstrated causal pathway in patients. The study describes a proposed mechanism and potential targets; it does not report clinical trials of any therapy. As an article shared ahead of the final version of record, its content is citable but subject to further editorial revision.
Even so, the work connects two active research threads: how thyroid hormone shapes liver metabolism, and how ferroptosis contributes to liver disease. By proposing that T3 acts as a transcriptional switch for an antioxidant defense cascade in hepatocytes, the study gives researchers a specific molecular handle for future investigations into hypothyroidism-associated liver injury and, more broadly, into ferroptosis-related liver conditions.
Subject of Research: How thyroid hormone deficiency promotes ferroptotic liver cell death in congenital hypothyroidism
Article Title: Hypothyroidism drives hepatic ferroptosis via disrupting THRβ/RXRβ–AMPKα1–GPX4 axis
Article References: Chen, C., Qin, S., Lin, Y., Liu, L., Jiang, Y., Yang, Y., Liang, K., Liu, J., Yang, S., Tao, C., Wang, X., Wu, T., Li, N., Wang, F., Lei, K., Zhang, Y., Zhao, J., & Wang, Y. (2026). Hypothyroidism drives hepatic ferroptosis via disrupting THRβ/RXRβ–AMPKα1–GPX4 axis. Cellular & Molecular Biology Letters. https://doi.org/10.1186/s11658-026-01024-5
Image Credits: AI Generated
DOI: 10.1186/s11658-026-01024-5
Keywords: congenital hypothyroidism, ferroptosis, liver injury, thyroid hormone T3, THRβ/RXRβ, AMPKα1, GPX4, lipid peroxidation, iron overload, pig model, hepatocytes, RSL3
News Source: Drew Townsend. (October 28, 2026). Low thyroid hormone triggers liver cell ferroptosis in congenital hypothyroidism study. Scienmag.
