Background: The dysregulated mechanistic target of rapamycin complex 1 (mTORC1) signaling plays a critical role in ferroptosis resistance and tumorigenesis. However, the precise underlying mechanisms still need to be fully understood. Methods: Endoplasmic reticulum oxidoreductase 1 alpha (ERO1α) expression in mTORC1-activated mouse embryonic fibroblasts, cancer cells, and laryngeal squamous cell carcinoma (LSCC) clinical samples was examined by quantitative real-time PCR (qRT–PCR), western blotting, immunofluorescence (IF), and immunohistochemistry. Extensive in vitro and in vivo experiments were carried out to determine the role of ERO1α and its downstream target, member 11 of the solute carrier family 7 (SLC7A11), in mTORC1-mediated cell proliferation, angiogenesis, ferroptosis resistance, and tumor growth. The regulatory mechanism of ERO1α on SLC7A11 was investigated via RNA-sequencing, a cytokine array, an enzyme-linked immunosorbent assay, qRT–PCR, western blotting, IF, a luciferase reporter assay, and a chromatin immunoprecipitation assay. The combined therapeutic effect of ERO1α inhibition and the ferroptosis inducer imidazole ketone erastin (IKE) on mTORC1-activated cells was evaluated using cell line-derived xenografts, LSCC organoids, and LSCC patient-derived xenograft models. Results: ERO1α is a functional downstream target of mTORC1. Elevated ERO1α induced ferroptosis resistance and exerted pro-oncogenic roles in mTORC1-activated cells via upregulation of SLC7A11. Mechanically, ERO1α stimulated the transcription of SLC7A11 by activating the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway. Moreover, ERO1α inhibition combined with treatment using the ferroptosis inducer IKE exhibited synergistic antitumor effects on mTORC1-activated tumors. Conclusions: The ERO1α/IL-6/STAT3/SLC7A11 pathway is crucial for mTORC1-mediated ferroptosis resistance and tumor growth, and combining ERO1α inhibition with ferroptosis inducers is a novel and effective treatment for mTORC1-related tumors.

Angiogenesis is a key characteristic of asthma airway remodeling. By releasing cationic granule proteins, such as major basic protein (MBP), activated eosinophils play a prominent role in asthma, but the underlying mechanisms are still not fully understood. In this study, we demonstrated that fibroblast growth factor-binding protein 1 (FGFBP1) was dramatically upregulated in airway epithelial cell lines treated by poly-L-arginine (PLA), a mimic of MBP. Elevated FGFBP1 expression was also detected in asthma clinical samples, as well as in ovalbumin (OVA)-induced chronic asthma mouse models. PLA enhanced FGFBP1 expression through activation of the mechanistic target of rapamycin complex 1-signal transducer and activator of transcription 3 (mTORC1-STAT3) signaling pathway. STAT3 transactivated FGFBP1 by directly binding to the promoter of the FGFBP1 gene. Furthermore, we identified that FGFBP1 secreted by PLA-treated airway epithelial cells served as a proangiogenesis factor. Lastly, we found the mTORC1-STAT3-FGFBP1 signaling pathway was activated in an OVA-induced chronic asthma model with airway remodeling features. Rapamycin treatment alleviated respiratory symptoms and reduced angiogenesis in asthmatic mice. Therefore, activation of the mTORC1-STAT3-FGFBP1 pathway in the airway epithelium contributes to the progress of angiogenesis and should be targeted for the treatment of asthma.

Background: Endoscopic thyroidectomy (ET) and robotic thyroidectomy (RT) yield similar perioperative outcomes. This study investigated how the learning curve (LC) affects perioperative outcomes between ET and RT, identifying factors that influence the LC. Materials and methods: Two researchers individually searched PubMed, EMBASE, Web of Science, and Cochrane Library for relevant studies published until February 2024. The Newcastle–Ottawa Scale assessed study quality. A random-effects model was used to compute the odds ratio and weighted mean difference (WMD). Poisson regression comparison of the number of surgeries (N _LC ) was required for ET and RT to reach the stable stage of the LC. Heterogeneity was measured using Cochran’s Q. Publication bias was tested using funnel plots, and sensitivity analysis assessed findings robustness. Subgroup analysis was done by operation type and patient characteristics. Results: This meta-analysis involved 33 studies. The drainage volume of ET was higher than that of RT (WMD=−17.56 [30.22, −4.49]). After reaching the N _LC , the operation time of ET and RT was shortened (ET: WMD=28.15 [18.04–38.26]; RT: WMD=38.53 [29.20–47.86]). Other perioperative outcomes also improved to varying degrees. Notably, RT showed more refined central lymph node resection (5.67 vs. 4.71), less intraoperative bleeding (16.56 ml vs. 42.30 ml), and incidence of transient recurrent laryngeal nerve injury (24.59 vs. 26.77). The N _LC of RT was smaller than that of ET (incidence-rate ratios [IRR]=0.64 [0.57–0.72]). CUSUM analysis (ET: IRR=0.84 [0.72–0.99]; RT: IRR=0.55 [0.44–0.69]) or a smaller number of respondents (ET: IRR=0.26 [0.15–0.46]; RT: IRR=0.51 [0.41–0.63]) was associated with smaller N _LC . In RT, transoral approach (IRR=2.73 [1.96–4.50]; IRR=2.48 [1.61–3.84]) and retroauricular approach (RAA) (IRR=2.13 [1.26–3.60]; IRR=1.78 [1.04–3.05]) had smaller N _LC compared to bilateral axillo-breast and transaxillary approach (TAA). In ET, the N _LC of RAA was smaller than that of TAA (IRR=1.61 [1.04–2.51]), breast approach (IRR=1.67 [1.06–2.64]), and subclavian approach (IRR=1.80 [1.03–3.14]). Conclusions: Rich surgical experience can improve surgical results of ET and RT. After reaching the N _LC , the perioperative outcomes of RT are better than those of ET. Study subjects, surgical approaches, and analysis methods can affect N _LC .

Head and neck squamous cell carcinoma (HNSCC) is a prevalent disease that has a low survival rate and high recurrence risk. Our study aims to investigate the expression and role of SEC11A in HNSCC. The expression of SEC11A was assessed in 18 pairs of cancerous and adjacent tissues by qRT-PCR and western blotting. Immunohistochemistry was performed in clinical specimen sections to evaluate the expression of SEC11A and its association with outcomes. Furthermore, the functional role of SEC11A in HNSCC tumor proliferation and progression was investigated using the in vitro cell model with lentivirus-mediated SEC11A knockdown. Colony formation and CCK8 assays were conducted to assess cell proliferation potential, while in vitro migration and invasion were examined using wound healing and transwell assays. To determine the tumor formation potential in vivo, a tumor xenograft assay was used. In contrast to adjacent normal tissues, SEC11A expression was significantly elevated in HNSCC tissues. SEC11A was mainly localized in the cytoplasm, and its expression was significantly associated with patient prognosis. SEC11A was silenced using shRNA lentivirus in TU212 and TU686 cell lines, and the gene knockdown was confirmed. A series of functional assays demonstrated that SEC11A knockdown reduced cell proliferation, migration and invasion ability in vitro. In addition, the xenograft assay demonstrated that SEC11A knockdown significantly inhibited tumor growth in vivo. Tumor tissue sections of mice showed decreased proliferation potential in the shSEC11A xenografts cells by immunohistochemistry. SEC11A knockdown decreased cell proliferation, migration and invasion in vitro and subcutaneous tumorigenesis in vivo. SEC11A is crucial to HNSCC proliferation and progression, and may serve as a new therapeutic target.

Head and neck squamous cell carcinoma (HNSCC) is often diagnosed at advanced stages, resulting in poor clinical outcomes. Ferroptosis resistance presents a major challenge in the treatment of HNSCC, highlighting the need to elucidate the mechanisms that enable HNSCC cells to evade ferroptosis. In this study, we conducted a genome-wide CRISPR–Cas9 knockout screen and identified trafficking protein particle complex subunit 4 (TRAPPC4) as a key regulator of ferroptosis resistance in HNSCC. Across a comprehensive set of experimental models, including HNSCC cell lines, patient-derived organoids, cell-derived xenografts, patient-derived xenografts, Trappc4 conditional knockout mice, and lymph node and lung metastasis models, TRAPPC4 promoted tumor progression by inhibiting ferroptosis. Mechanistically, TRAPPC4 decreased chromatin accessibility at a distal regulatory element upstream of TRIM55, thereby limiting FOS-dependent transcription. This repression reduced TRIM55-mediated GPX4 ubiquitination and degradation, resulting in GPX4 stabilization and ferroptosis resistance. Structure-based high-throughput virtual screening identified pitavastatin (PTV) calcium as a TRAPPC4-binding compound that promoted TRAPPC4 degradation. Notably, PTV calcium synergized with the ferroptosis inducer RSL3 to enhance ferroptotic activity and suppress HNSCC progression. These findings delineate a TRAPPC4–FOS–TRIM55–GPX4 signaling axis that drives ferroptosis resistance and tumor progression and highlight TRAPPC4 as a promising therapeutic target for ferroptosis-based intervention in HNSCC. Significance: TRAPPC4 enables head and neck squamous cell carcinoma to resist ferroptosis by regulating TRIM55-mediated GPX4 degradation, providing a potential therapeutic target to inhibit cancer progression.

TRAPPC4 knockout accelerates GPX4 protein degradation.