Programmed cell death represents a precisely regulated and active cellular demise, governed by a complex network of specific genes and proteins. The identification of multiple forms of programmed cell death has significantly advanced the understanding of its intricate mechanisms, as demonstrated in recent studies. A thorough grasp of these processes is essential across various biological disciplines and in the study of diseases. Nonetheless, despite notable progress, the exploration of the relationship between programmed cell death and disease, as well as its clinical application, are still in a nascent stage. Therefore, further exploration of programmed cell death and the development of corresponding therapeutic methods and strategies holds substantial potential. Our review provides a detailed examination of the primary mechanisms behind apoptosis, autophagy, necroptosis, pyroptosis, and ferroptosis. Following this, the discussion delves into biological functions and diseases associated dysregulated programmed cell death. Finally, we highlight existing and potential therapeutic targets and strategies focused on cancers and neurodegenerative diseases. This review aims to summarize the latest insights on programmed cell death from mechanisms to diseases and provides a more reliable approach for clinical transformation.

Background: Nasopharyngeal carcinoma (NPC) is a malignant tumor of epithelial origin in head and neck with high incidence rate in Southern China. C2orf40 has been identified as a tumor suppressor gene in many cancers. However, the roles of C2orf40 in nasopharyngeal carcinoma has not been studied. Methods: In this study, a bioinformatics analysis was performed to identify the differentially expressed genes in NPC. The quantitative methylation levels was detected using pyrosequencing. qRT-PCR, western blotting, immunohistochemistry and immunofluorescence were used to detect the expression level of related RNA and proteins. Cell proliferation was detected using CCK-8 assay, and colony formation capability was detected using colony formation assays. Cell migration and invasion were analyzed using wound-healing and Transwell assays, respectively. The apoptosis level of cells was assessed using TUNEL staining. Endogenous DNA damage and repair were assessed by the comet assay. Cell cycle analyses carried out by flow cytometry. Finally, We used a xenograft nude mouse to verify the roles of C2orf40 in chemoresistance and radioresistance in vivo. Results: We found that the C2orf40 expression was significantly downregulated in NPC tissues and inversely associated with a poor prognosis. In vivo and in vitro functional experiments confirmed that overexpression of C2orf40 significantly inhibited the migration and invasion of NPC cells, and promoted their sensitivity to radiotherapy and chemotherapy of NPC cells. Mechanically, the expression level of C2orf40 was negatively correlated with the expression levels of CCNE1 and CDK1. Overexpression of C2orf40 induced cell cycle arrest of NPC cells at G/M phase. In addition, C2orf40 can down-regulated the expression levels of homologous recombination-related proteins (BRCA1, BRCA2, RAD51, and CDC25A) and inhibited the activity of the PI3K/AKT/mTOR signaling pathway. Conclusion: The results clarified the biological functions and mechanisms of C2orf40, as a tumor suppressor gene, in NPC, and provided a potential molecular target for improving the sensitivity of NPC to radiotherapy and chemotherapy.

Background: The metastatic characteristics of hypopharyngeal squamous cell carcinoma (HSCC) lead to many diagnostic and therapeutic challenges, while functional long non-coding RNAs (lncRNAs) can provide effective strategies for its diagnosis and treatment. Methods: RT-qPCR, Western blot, immunohistochemistry, and an immunofluorescence assay were used to detect the related gene expression. Flow cytometry was used to measure the percentage of CD8⁺ and CD4⁺ T cells. CCK-8 and transwell assays were performed to analyze the role of HOXA11-AS1. The targeted relationship of the FOSL1/PD-L1 promoter was measured by ChIP and dual-luciferase reporter assays. RNA pulldown and RIP assays were used to measure the interaction between HOXA11-AS1, FOSL1, and PTBP1. A tumor xenograft study was used to analyze HOXA11-AS1 function in vivo. Results: HOXA11-AS1, PD-L1, and FOSL1 were upregulated in HSCC, and HOXA11-AS1 positively correlated with PD-L1. HOXA11-AS1 knockdown upregulated CD8⁺ T cells through an increase in IFN-γ concentration while decreasing the proliferation, migration, and invasion of HSCC cells. FOSL1 bound the PD-L1 promoter, increasing gene expression. HOXA11-AS1 enhanced the stability of FOSL1 mRNA by binding to PTBP1. HOXA11-AS1 or PTBP1 overexpression increased FOSL1 and PD-L1 expression. PD-L1 knockdown arrested the inhibiting function of HOXA11-AS1 overexpression on CD8⁺ T cell content. HOXA11-AS1 knockdown inhibited immune escape and metastasis through PD-L1 regulation by downregulating FOSL1 in vivo. Conclusion: HOXA11-AS1 promoted PD-L1 expression by upregulating FOSL1 levels through PTBP1, thereby facilitating immune escape, proliferation, and metastasis of HSCC cells.

The journal retracts the article “HOXA11-AS1 Promotes PD-L1-Mediated Immune Escape and Metastasis of Hypopharyngeal Carcinoma by Facilitating PTBP1 and FOSL1 Association”

Background: Hypopharyngeal carcinoma is the worst type of head and neck squamous cell carcinoma. It is necessary to identify the key molecular targets related to the carcinogenesis and development of hypopharyngeal carcinoma. Methods: Differentially expressed lncRNAs in hypopharyngeal carcinoma were selected by microarray, and lncRNA-associated proteins were found by RIP assay. Colony formation, CCK-8, wound healing and Transwell assays were performed to detect the effects of lncRNA and its associated protein on cell proliferation and migration in vitro. Downstream pathways of lncRNA and its associated protein were detected by WB. Through a subcutaneous tumor model, the effects of lncRNA and its associated protein on cell proliferation were detected. The expressions of lncRNA and its associated protein in hypopharyngeal cancer tissues were detected by qRT-PCR and immunohistochemistry assays, respectively, and survival analyses were performed by Kaplan-Meier curve. Results: A total of 542 and 265 lncRNAs were upregulated and downregulated in microarrays, respectively. LncRNA NR120519 was upregulated and promoted cell proliferation and migration of hypopharyngeal carcinoma in vitro and cell proliferation in vivo. RIP and WB assays showed that KRT17 was associated with and blocked by NR120519.The silencing of KRT17 promoted cell proliferation and the migration of hypopharyngeal carcinoma in vitro and cell proliferation in vivo by activating the AKT/mTOR pathway and epithelial-mesenchymal transformation (EMT). Finally, the NR120519 high expression and KRT17 low expression groups showed shorter overall survival. Conclusion: NR120519 activated the AKT/mTOR pathway and EMT by blocking KRT17 to promote cell proliferation and the migration of hypopharyngeal carcinoma.