Solid tumors have developed robust ferroptosis resistance. The mechanism underlying ferroptosis resistance regulation in solid tumors, however, remains elusive. Here, we report that the hypoxic tumor microenvironment potently promotes ferroptosis resistance in solid tumors in a hypoxia-inducible factor 1α (HIF-1α)-dependent manner. In combination with HIF-2α, which promotes tumor ferroptosis under hypoxia, HIF-1α is the main driver of hypoxia-induced ferroptosis resistance. Mechanistically, HIF-1α-induced lactate contributes to ferroptosis resistance in a pH-dependent manner that is parallel to the classical SLC7A11 and FSP1 systems. In addition, HIF-1α also enhances transcription of SLC1A1, an important glutamate transporter, and promotes cystine uptake to promote ferroptosis resistance. In support of the role of hypoxia in ferroptosis resistance, silencing HIF-1α sensitizes mouse solid tumors to ferroptosis inducers. In conclusion, our results reveal a mechanism by which hypoxia drives ferroptosis resistance and identify the combination of hypoxia alleviation and ferroptosis induction as a promising therapeutic strategy for solid tumors.

Colorectal cancer (CRC) is highly resistant to ferroptosis, which hinders the application of anti‐ferroptosis therapy. Through drug screening, it is found that histone deacetylase inhibitor (HDACi) significantly sensitized CRC to ferroptosis. The combination of HDACi and ferroptosis inducers synergically suppresses CRC growth both in vivo and in vitro. Mechanically, HDACi reduces ferroptosis suppressor protein (FSP1) by promoting its mRNA degradation. Specifically, it is confirmed that HDACi specifically targets HDAC1 and promotes the H3K27ac modification of fat mass‐ and obesity‐associated gene (FTO) and AlkB Homolog 5, RNA Demethylase (ALKBH5), which results in significant activation of FTO and ALKBH5. The activation of FTO and ALKBH5 reduces N6‐methyladenosine (m⁶A) modification on FSP1 mRNA, leading to its degradation. Crucially, lactylation of HDAC1^K412 is essential for ferroptosis regulation. Both Vorinostat (SAHA) and Trichostatin A (TSA) notably diminish HDAC1^K412 lactylation in comparison to other HDAC1 inhibitors, exhibiting a consistent trend of increasing susceptibility to ferroptosis. In conclusion, the research reveals that HDACi decreases HDAC1^K412 lactylation to sensitize CRC to ferroptosis and that the combination of HDACi and ferroptosis inducers can be a promising therapeutic strategy for CRC.

In this study, we exploited the Inception-v3 deep convolutional neural network (DCNN) model to differentiate cervical lymphadenopathy using cytological images. A dataset of 80 cases was collected through the fine-needle aspiration (FNA) of enlarged cervical lymph nodes, which consisted of 20 cases of reactive lymphoid hyperplasia, 24 cases of non-Hodgkin's lymphoma (NHL), 16 cases of squamous cell carcinoma (SCC), and 20 cases of adenocarcinoma. The images were cropped into fragmented images and divided into a training dataset and a test dataset. Inception-v3 was trained to make differential diagnoses and then tested. The features of misdiagnosed images were further analysed to discover the features that may influence the diagnostic efficiency of such a DCNN. A total of 742 original images were derived from the cases, from which a total of 7,934 fragmented images were cropped. The classification accuracies for the original images of reactive lymphoid hyperplasia, NHL, SCC and adenocarcinoma were 88.46%, 80.77%, 89.29% and 100%, respectively. The total accuracy on the test dataset was 89.62%. Three fragmented images of reactive lymphoid hyperplasia and three fragmented images of SCC were misclassified as NHL. Three fragmented images of NHL were misclassified as reactive lymphoid hyperplasia, one was misclassified as SCC, and one was misclassified as adenocarcinoma. In summary, after training with a large dataset, the Inception-v3 DCNN model showed great potential in facilitating the diagnosis of cervical lymphadenopathy using cytological images. Analysis of the misdiagnosed cases revealed that NHL was the most challenging cytology type for DCNN to differentiate.

Although anaplastic thyroid cancer (ATC) constitutes only 1–2% of all thyroid malignancies, it is associated with an exceptionally high mortality rate, accounting for 14–39% of thyroid cancer-related deaths. In this study, we identified the critical role of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in ATC progression. Proteomic analysis revealed E-cadherin as a key mediator of PCSK9-driven malignancy in ATC. Mechanistically, PCSK9 promotes the degradation of E-cadherin through the lysosomal pathway. Furthermore, the loss of the p53 function, particularly the R248Q mutation, de-repressed PCSK9 expression at the transcriptional level. Notably, the PCSK9 inhibitor PF-846 considerably suppressed ATC proliferation and metastasis in both in vitro and in vivo models. In conclusion, PCSK9 enhances ATC malignancy by regulating E-cadherin degradation via the lysosomal pathway, underscoring its potential as a promising therapeutic target.