Transferrin receptor serves a role in promoting PANoptosis in thyroid cancer

PANoptosis is an emerging form of regulated cell death (RCD) that results from the interaction between necrosis, apoptosis and pyroptosis. The transferrin receptor (TFRC) is a suppressor in thyroid cancer (TC) and is involved in several RCD pathways, including ferroptosis, apoptosis, cuproptosis and necrosis. The present study aimed to assess how TFRC influences PANoptosis in TC and evaluate its underlying molecular mechanisms. Bioinformatics analyses were performed to identify coding genes associated with the expression of PANoptosis markers (Z-DNA-binding protein 1 and absent in melanoma 2) in The Cancer Genome Atlas-Thyroid Cancer (TCGA-THCA) dataset. Techniques such as PI/Calcein-AM and YO-PRO-1/PI staining, and western blotting were used to assess how TFRC influences PANoptosis in TC cells. Additionally, mRNA sequencing (mRNA-seq) was employed to identify differentially expressed (DE)-mRNA associated with TFRC. A total of 729 and 1,568 coding genes in the TCGA-THCA dataset demonstrated a significant association with ZBP-1 and AIM2 expression, respectively, involving regulation of immunity, apoptosis and necroptosis. Among these, TFRC was identified as a prognostic biomarker for TC and was downregulated in TC tissues and cells. Overexpression of TFRC increased TC cells undergoing pyroptosis, apoptosis and necroptosis, whilst it decreased the number of viable cells. Additionally, TFRC overexpression was associated with an elevation in the expression of cleaved-caspase (CASP)1, CASP1, cleaved-CASP3, CASP3, phospho-mixed lineage kinase domain-like and total-receptor-interacting serine/threonine-protein kinase 3, whereas TFRC knockdown was associated with the opposite effects. mRNA-seq identified 828 DE-mRNAs associated with TFRC. Enrichment analysis revealed that these DE-miRNAs regulate cell cycle, apoptosis, necrotic apoptosis, pyroptosis, oxidative stress and immunity. Furthermore, in the protein-protein interaction network constructed from DE-mRNAs, genes such as <i>CD34</i>, lactate dehydrogenase A (<i>LDHA</i>) and low-density lipoprotein receptor (<i>LDLR</i>) were identified as TFRC-interacting partners, and their expression demonstrated a positive association with TFRC. Furthermore, TFRC knockdown effectively reduced the levels of these genes. In conclusion, TFRC facilitates PANoptosis in TC, potentially through interactions with genes such as <i>CD34, LDHA</i> and <i>LDLR</i>.