Although some pyroptosis-related (PR) prognostic models for cancers have been reported, pyroptosis-based features have not been fully discovered at the single-cell level in hepatocellular carcinoma (HCC). In this study, by deeply integrating single-cell and bulk transcriptome data, we systematically investigated significance of the shared pyroptotic signature at both single-cell and bulk levels in HCC prognosis. Based on the pyroptotic signature, a robust PR risk system was constructed to quantify the prognostic risk of individual patient. To further verify capacity of the pyroptotic signature on predicting patients’ prognosis, an attention mechanism-based deep neural network classification model was constructed. The mechanisms of prognostic difference in the patients with distinct PR risk were dissected on tumor stemness, cancer pathways, transcriptional regulation, immune infiltration and cell communications. A nomogram model combining PR risk with clinicopathologic data was constructed to evaluate the prognosis of individual patients in clinic. The PR risk could also evaluate therapeutic response to neoadjuvant therapies in HCC patients. In conclusion, the constructed PR risk system enables a comprehensive assessment of tumor microenvironment characteristics, accurate prognosis prediction and rational therapeutic options in HCC.

Most cancers and neoplastic progenitor cells have elevated telomerase activity and preservation of telomeres that promote cellular immortality, making telomerase a rational target for the treatment of cancer. Imetelstat is a first‐in‐class, 13‐mer oligonucleotide that binds with high affinity to the template region of the RNA component of human telomerase and acts as a competitive inhibitor of human telomerase enzymatic activity. Pharmacokinetics, pharmacodynamics, exposure‐response analyses, efficacy, and safety of imetelstat have been evaluated in vitro, in vivo, and clinically in solid tumor and hematologic malignancies, including lower‐risk myelodysplastic syndromes (LR‐MDS) and myeloproliferative neoplasms. Imetelstat was approved in the United States in June 2024 for the treatment of adult patients with LR‐MDS with transfusion‐dependent anemia requiring four or more red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis‐stimulating agents, with a recommended dosing regimen of 7.1 mg/kg administered via 2‐h intravenous infusion every 4 weeks. In the pivotal trial, significantly more patients treated with imetelstat versus placebo achieved ≥8‐week and ≥24‐week red blood cell‐transfusion independence, and imetelstat was associated with a manageable safety profile characterized primarily by short‐lived and manageable neutropenia and thrombocytopenia. This mini‐review summarizes the mechanism of action, pharmacokinetic and pharmacodynamic characteristics, clinical development, and clinical efficacy and safety data of imetelstat.

Background: Alcohol-associated liver disease (ALD) is a syndrome of progressive inflammatory liver injury and vascular remodeling associated with long-term heavy intake of ethanol. Elevated miR-34a expression, macrophage activation, and liver angiogenesis in ALD and their correlation with the degree of inflammation and fibrosis have been reported. The current study aims to characterize the functional role of miR-34a-regulated macrophage- associated angiogenesis during ALD. Methods & Results: We identified that knockout of miR-34a in 5 weeks of ethanol-fed mice significantly decreased the total liver histopathology score and miR-34a expression, along with the inhibited liver inflammation and angiogenesis by reduced macrophage infiltration and CD31/VEGF-A expression. Treatment of murine macrophages (RAW 264.7) with lipopolysaccharide (20 ng/mL) for 24 h significantly increased miR-34a expression, along with the enhanced M1/M2 phenotype changes and reduced Sirt1 expression. Silencing of miR-34a significantly increased oxygen consumption rate (OCR) in ethanol treated macrophages, and decreased lipopolysaccharide-induced activation of M1 phenotypes in cultured macrophages by upregulation of Sirt1. Furthermore, the expressions of miR-34a and its target Sirt1, macrophage polarization, and angiogenic phenotypes were significantly altered in isolated macrophages from ethanol-fed mouse liver specimens compared to controls. TLR4/miR-34a knockout mice and miR-34a Morpho/AS treated mice displayed less sensitivity to alcohol-associated injury, along with the enhanced Sirt1 and M2 markers in isolated macrophages, as well as reduced angiogenesis and hepatic expressions of inflammation markers MPO, LY6G, CXCL1, and CXCL2. Conclusion: Our results show that miR-34a-mediated Sirt1 signaling in macrophages is essential for steatohepatitis and angiogenesis during alcohol-induced liver injury. These findings provide new insight into the function of microRNA-regulated liver inflammation and angiogenesis and the implications for reversing steatohepatitis with potential therapeutic benefits in human alcohol-associated liver diseases.

Tax1 banding protein 1 (Tax1bp1) was originally identified as an NF-κB regulatory protein that participated in inflammatory, antiviral and innate immune processes. Tax1bp1 also functions as an autophagy receptor that plays a role in autophagy. Our previous study shows that Tax1bp1 protects against cardiomyopathy in STZ-induced diabetic mice. In this study we investigated the role of Tax1bp1 in heart failure. Pressure overload-induced heart failure model was established in mice by aortic banding (AB) surgery, and angiotensin II (Ang II)-induced heart failure model was established by infusion of Ang II through osmotic minipump for 4 weeks. We showed that the expression levels of Tax1bp1 in the heart were markedly increased 2 and 4 weeks after AB surgery. Knockdown of Tax1bp1 in mouse hearts significantly ameliorated both AB- and Ang II infusion-induced heart failure parameters. On the contrary, AB-induced heart failure was aggravated in cardiac-specific Tax1bp1 transgenic mice. Similar results were observed in neonatal rat cardiomyocytes (NRCMs) under Ang II insult. We demonstrated that the pro-heart failure effect of Tax1bp1 resulted from its interaction with the E3 ligase ITCH to promote the transcription factor P73 ubiquitination and degradation, causing enhanced BCL2 interacting protein 3 (BNIP3)-mediated cardiomyocyte apoptosis. Knockdown ITCH or BNIP3 in NRCMs significantly reduced Ang II-induced apoptosis in vitro. Similarly, BNIP3 knockdown attenuated heart failure in cardiac-specific Tax1bp1 transgenic mice. In the left ventricles of heart failure patients, Tax1bp1 expression level was significantly increased; Tax1bp1 gene expression was negatively correlated with left ventricular ejection fraction in heart failure patients. Collectively, the Tax1bp1 increase in heart failure enhances ITCH-P73-BNIP3-mediated cardiomyocyte apoptosis and induced cardiac injury. Tax1bp1 may serve as a potent therapeutic target for the treatment of heart failure. • Cardiac Tax1bp1 transgene mice were more vulnerable to cardiac dysfunction under stress. • Cardiac Tax1bp1 transgene mice were more vulnerable to cardiac dysfunction under stress. • Knockout of Tax1bp1 in mouse hearts ameliorated heart failure induced by pressure overload. • Tax1bp1 interacts with the E3 ligase Itch to promote P73 ubiquitination and degradation, causing enhanced BNIP3-mediated apoptosis. • Tax1bp1 may become a target of new therapeutic methods for treating heart failure.