Jinrong Zhu

PANoptosis represents a distinct form of programmed cell death (PCD) that is characterized by the integration of key features from apoptosis, pyroptosis, and necroptosis but cannot be fully explained by any single cell death pathway. A key trigger of PANoptosis is the assembly and activation of the PANoptosome. To date, four types of PANoptosomes have been identified, including PANoptosomes nucleated by Z-DNA binding protein 1 (ZBP1), absent in melanoma 2 (AIM2), receptor-interacting protein kinase 1 (RIPK1), and NOD-like receptor protein 12 (NLRP12). This review summarizes current advances in the molecular regulatory mechanisms underlying PANoptosis and delineates the assembly and activation processes of several PANoptosome complexes. Furthermore, the role of PANoptosis in various pathologic conditions, such as infectious diseases, autoimmune disorders, neurodegenerative diseases, and cancer, are discussed. Recent preclinical and clinical advances in targeting the PANoptosis pathway through small molecule inhibitors, nanomedicines, and combination therapies for the treatment of infectious diseases, inflammatory conditions, and malignancies are also highlighted. However, current research involving the mechanisms underlying PANoptosis are preliminary and the clinical translation faces significant challenges, necessitating further in-depth exploration. This review demonstrates that targeting molecular components and signaling pathways of PANoptosis represents a highly promising therapeutic strategy, aiming to provide a theoretical foundation for the development of novel clinical treatments for related diseases.

A new type of nonapoptotic, iron-dependent cell death induced by lipid peroxidation is known as ferroptosis. Numerous pathological processes, including inflammation and cancer, have been demonstrated to be influenced by changes in the ferroptosis-regulating network. Long non-coding RNAs (LncRNAs) are a group of functional RNA molecules that are not translated into proteins, which can regulate gene expression in various manners. An increasing number of studies have shown that lncRNAs can interfere with the progression of ferroptosis by modulating ferroptosis-related genes directly or indirectly. Despite evidence implicating lncRNAs in cancer and inflammation, studies on their mechanisms and therapeutic potential remain scarce. We investigate the mechanisms of lncRNA-mediated regulation of inflammation and cancer immunity, assessing the feasibility and challenges of lncRNAs as therapeutic targets in these conditions.

The fundamental biological characteristics of tumor cells are characterized by irregularities in signaling and metabolic pathways, which are evident through increased glucose uptake, altered mitochondrial function, and the ability to evade growth signals. Interventions such as fasting or fasting-mimicking diets represent a promising strategy that can elicit distinct responses in normal cells compared to tumor cells. These dietary strategies can alter the circulating levels of various hormones and metabolites, including blood glucose, insulin, glucagon, growth hormone, insulin-like growth factor, glucocorticoids, and epinephrine, thereby potentially exerting an anticancer effect. Additionally, elevated levels of insulin-like growth factor-binding proteins and ketone bodies may increase tumor cells’ dependence on their own metabolites, ultimately leading to their apoptosis. The combination of fasting or fasting-mimicking diets with radiotherapy or chemotherapeutic agents has demonstrated enhanced anticancer efficacy. This paper aims to classify fasting, elucidate the mechanisms that underlie its effects, assess its impact on various cancer types, and discuss its clinical applications. We will underscore the differential effects of fasting on normal and cancer cells, the mechanisms responsible for these effects, and the imperative for clinical implementation.

Ferroptosis represents a distinct form of programmed cell death triggered by excessive iron accumulation and lipid peroxidation-induced damage. This mode of cell death differentiates from classical programmed cell death in terms of morphology and biochemistry. Ferroptosis stands out for its exceptional biological characteristics and has garnered extensive research and conversations as a form of programmed cell death. Its dysfunctional activation is closely linked to the onset of diseases, particularly inflammation and cancer, making ferroptosis a promising avenue for combating these conditions. As such, exploring ferroptosis may offer innovative approaches to treating cancer and inflammatory diseases. Our review provides insights into the relevant regulatory mechanisms of ferroptosis, examining the impact of ferroptosis-related factors from both physiological and pathological perspectives. Describing the crosstalk between ferroptosis and tumor- and inflammation-associated signaling pathways and the potential of ferroptosis inducers in overcoming drug-resistant cancers are discussed, aiming to inform further novel therapeutic directions for ferroptosis in relation to inflammatory and cancer diseases.

Background: Chemoresistance is a significant factor contributing to tumor recurrence and treatment failure in non-small cell lung cancer (NSCLC). The phosphofructokinase, platelet (PFKP) is highly expressed in NSCLC and is associated with a poor prognosis. Exploring the molecular mechanism and identifying effective strategies to overcome chemoresistance will have important clinical significance in improving the diagnosis and treatment of NSCLC. Methods: The correlation between PFKP and cisplatin resistance in NSCLC patients was assessed by organoids and immunohistochemistry. The impact of PFKP on the prognosis of NSCLC patients was analyzed using The Cancer Genome Atlas (TCGA) database. In NSCLC cell lines, the expression of PFKP was modulated using lentivirus, and cisplatin sensitivity was assessed by flow cytometry. Subsequently, the therapeutic effect of cisplatin was tested in BALB/c nude mice implanted subcutaneously with tumor cells. We performed luciferase assay and immunohistochemistry (IHC) to investigate the correlation between PFKP and ABCC2 (ATP-binding cassette sub-family C member 2). Results: Overexpression of PFKP was correlated with poorer survival rates in NSCLC patients who received platinum-based chemotherapy. Using NSCLC organoid, we found that the expression of PFKP was elevated in cisplatin (CDDP)-resistant patients with NSCLC. Overexpression of PFKP decreased the sensitivity of NSCLC cells to CDDP, while genetic inhibition of PFKP enhanced CDDP sensitivity both in vitro and in vivo. Furthermore, we found that PFKP upregulated ABCC2 by increasing the levels of phosphorylation of IκBα and nuclear p65 NF-κB subunit protein. Conclusions: PFKP can regulate the expression of ABCC2 through the activation of NF-κB, which in turn promotes chemoresistance in NSCLC. PFKP has the potential to be a personalized therapeutic target for NSCLC patients with chemoresistance.

CircRNAs are a class of endogenous long non-coding RNAs with a single-stranded circular structure. Most circRNAs are relatively stable, highly conserved, and specifically expressed in tissue during the cell and developmental stages. Many circRNAs have been discovered in OSCC. OSCC is one of the most severe and frequent forms of head and neck cancer today, with a poor prognosis and low overall survival rate. Due to its prevalence, OSCC is a global health concern, characterized by genetic and epigenomic changes. However, the mechanism remains vague. With the advancement of biotechnology, a large number of circRNAs have been discovered in mammalian cells. CircRNAs are dysregulated in OSCC tissues and thus associated with the clinicopathological characteristics and prognosis of OSCC patients. Research studies have demonstrated that circRNAs can serve as biomarkers for OSCC diagnosis and treatment. Here, we summarized the properties, functions, and biogenesis of circRNAs, focusing on the progress of current research on circRNAs in OSCC.

Chemo-resistance has been identified as a crucial factor contributing to tumor recurrence and a leading cause of worse prognosis in patients with ESCC. Therefore, unravel the critical regulators and effective strategies to overcome drug resistance will have a significant clinical impact on the disease. In our study we found that RNF149 was upregulated in ESCC and high RNF149 expression was associated with poor prognosis with ESCC patients. Functionally, we have demonstrated that overexpression of RNF149 confers CDDP resistance to ESCC; however, inhibition of RNF149 reversed this phenomenon both in vitro and in vivo. Mechanistically, we demonstrated that RNF149 interacts with PH domain and leucine rich repeat protein phosphatase 2 (PHLPP2) and induces E3 ligase-dependent protein degradation of PHLPP2, substantially activating the PI3K/AKT signalling pathway in ESCC. Additionally, we found that inhibition of PI3K/AKT signalling pathway by AKT siRNA or small molecule inhibitor significantly suppressed RNF149-induced CDDP resistance. Importantly, RNF149 locus was also found to be amplified not only in ESCC but also in various human cancer types. Our data suggest that RNF149 might function as an oncogenic gene. Targeting the RNF149/PHLPP2/PI3K/Akt axis may be a promising prognostic factor and valuable therapeutic target for malignant tumours.