Qiang Luo

Punicalagin, a major ellagitannin enriched in pomegranate ( Punica granatum L.) peel, has been implicated in cellular redox regulation, yet its integrated mechanism against oxidative hepatocellular injury remains insufficiently defined. Here, we combined network pharmacology, molecular docking, and in vitro validation to elucidate the protective actions of punicalagin against hydrogen peroxide (H ₂ O ₂ )–induced injury in HepG2 cells. Punicalagin pretreatment markedly improved cell viability and suppressed intracellular reactive oxygen species accumulation following oxidative challenge. This protection was associated with improved mitochondrial function. Flow cytometry further demonstrated that punicalagin attenuated H ₂ O ₂ ‐triggered apoptosis, consistent with modulation of the mitochondrial apoptotic cascade as evidenced by an increased Bcl‐2/Bax balance and reduced caspase‐3 activation. Punicalagin also enhanced autophagy, as indicated by increased LC3B‐II and decreased p62. Network pharmacology identified overlapping targets between punicalagin and liver injury, with enrichment analyses highlighting PI3K/AKT‐related signaling; docking predicted favorable binding of punicalagin to AKT1. Mechanistically, punicalagin blunted oxidative stress–induced phosphorylation of PI3K, AKT, and mTOR without altering total protein abundance. Importantly, pharmacological reactivation of AKT using SC79 mitigated punicalagin‐induced autophagy, supporting a pathway‐dependent mode of action. Collectively, these findings indicate that punicalagin alleviates oxidative hepatocellular injury, supporting its potential as a food‐derived bioactive for oxidative stress–related liver dysfunction.

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with limited therapeutic options. Microtubule‐associated serine/threonine kinase‐like ( MASTL ), a pivotal regulator of mitosis, remains poorly characterized in HCC. This study aimed to elucidate the clinical significance, biological functions, and molecular mechanisms of MASTL in HCC progression. Bioinformatics analysis of TCGA and ICGC datasets revealed MASTL overexpression correlated with advanced tumor stage and served as an independent prognostic factor. Functional studies demonstrated that MASTL knockdown significantly disrupts HCC cell proliferation, increases the incidence of abnormal mitotic events, and amplifies DNA damage, collectively driving mitotic catastrophe (MC) and subsequent cell death. Mechanistically, MASTL regulated paclitaxel sensitivity by modulating ENSA phosphorylation and PP2A‐B55α activity, with PP2A‐B55α knockdown reversing MASTL deficiency‐induced MC. Transcriptional regulation analysis identified E2F1 as a direct activator of MASTL expression, confirmed by ChIP‐qPCR and dual‐luciferase reporter assays. These findings establish MASTL as a critical oncogene in HCC through the E2F1‐MASTL‐PP2A‐B55α axis, suggesting its potential as both a prognostic biomarker and therapeutic target for HCC. Future studies should explore MASTL inhibitors in combination with conventional chemotherapy to overcome drug resistance in HCC patients.

Immune checkpoint blockade (ICB) offers an in vivo approach to activate CD8 ⁺ tumor-infiltrating lymphocytes (CD8 ⁺ TILs) in cases of advanced non–small cell lung cancer (NSCLC). A large fraction of NSCLC patients is unresponsive to ICBs and relapse due to the development of dysfunctional CD8 ⁺ TILs with impaired cytotoxicity. Therefore, an improved understanding of regulator(s) that favor the development of cytotoxic T _eff cells over dysfunctional CD8 ⁺ TILs is required for the success of ICB therapy in NSCLC patients. Here, our metaVIPER-based scRNA-seq analysis of deep CD8 ⁺ cell scRNA-seq data from 14 treatment-naïve NSCLC patients revealed that the master regulon ZEB2 may drive CD8 ⁺ differentiation along the cytotoxic effector trajectory in NSCLC tumors. In vitro, ZEB2 acts downstream of T-bet to stimulate lung tumor-reactive T _eff cell differentiation. This T-bet/ZEB2 axis displays immunotherapeutic effects on KP.SIY lung tumors independent of ICB therapy and mediates the therapeutic effects of murine serum albumin-fused IL-2 + IL-12 combination immunotherapy (IL2-MSA + IL12-MSA) in mice. IL2-MSA + IL12-MSA operates through a parallel STAT4/FOXO1-mediated mechanism that promotes CD8 ⁺ TIL T-bet/ZEB2 expression and lung tumor-reactive T _eff cell differentiation. In conclusion, immunotherapeutic regimens that support ZEB2 activity in CD8 ⁺ cells may show promise in NSCLC patients.

Acute monocytic leukaemia, a subtype of acute myeloid leukaemia (AML), is a highly aggressive malignancy characterised by a poor prognosis, primarily due to the ability of leukaemic cells to evade immune surveillance. In this study, we demonstrate that homoharringtonine (HHT), an FDA‐approved therapeutic agent for chronic myeloid leukaemia (CML), inhibits this immune evasion by targeting the FTO/m6A/LILRB4 signalling pathway in monocytic AML. Utilising RNA sequencing (RNA‐seq) and various functional assays, we reveal that HHT treatment significantly reduces LILRB4 expression at both the RNA and protein levels, suggesting that the effects of HHT on LILRB4 are distinct from its well‐established role as a protein synthesis inhibitor. Mechanistically, HHT treatment markedly increases global levels of RNA m6A in THP‐1 cells by promoting the degradation of FTO, which subsequently diminishes the expression of its downstream targets, MLL1 and LILRB4. Furthermore, in vitro and in vivo analyses employing monocytic AML cell lines, mouse‐derived AML xenograft models, and patient samples collectively support the conclusion that HHT suppresses immune evasion in monocytic AML by reducing LILRB4 expression. Importantly, the downregulation of LILRB4 resulting from HHT treatment enhances the susceptibility of THP‐1 cells to CD8 ⁺ T cell cytotoxicity, accompanied by increased markers of immune activation. Overall, our findings position HHT as a promising clinical agent for enhancing CD8 ⁺ T cell‐based cancer immunotherapy by mitigating immune evasion in monocytic AML.

Acute monocytic leukemia (AML-M5), a subtype of acute myeloid leukemia, is a highly aggressive malignancy characterized by a poor prognosis, primarily due to the ability of leukemic cells to evade immune surveillance. In this study, we demonstrate that homoharringtonine (HHT), an FDA-approved therapeutic agent for chronic myeloid leukemia (CML), inhibits this immune evasion by targeting the FTO/m6A/LILRB4 signaling pathway in monocytic AML. Utilizing RNA sequencing (RNA-seq) and various functional assays, we reveal that HHT treatment significantly reduces LILRB4 expression at both the RNA and protein levels, suggesting that the effects of HHT on LILRB4 are distinct from its well-established role as a protein synthesis inhibitor. Mechanistically, HHT treatment markedly increases global levels of RNA m6A in THP-1 cells by promoting the degradation of FTO, which subsequently diminishes the expression of its downstream targets, MLL1 and LILRB4. Furthermore, in vitro and in vivo analyses employing monocytic AML cell lines, mouse-derived AML xenograft models, and patient samples collectively support the conclusion that HHT suppresses immune evasion in monocytic AML by reducing LILRB4 expression. Importantly, the downregulation of LILRB4 resulting from HHT treatment enhances the susceptibility of THP-1 cells to CD8 ⁺ T cell cytotoxicity, accompanied by increased markers of immune activation. Overall, our findings position HHT as a promising clinical agent for enhancing CD8 ⁺ T cell-based cancer immunotherapy by mitigating immune evasion in monocytic AML. Graphical

HCC is one of the most common malignant tumors. The life and health of humans are gravely threatened by HCC because of its hidden onset, high recurrence rate, poor therapeutic effect, and high mortality. It is essential to explore the particular pathological mechanisms of HCC in order to increase the rate of early diagnosis and enhance patient therapy outcomes. Recent research has demonstrated that SCUBE3 can influence HCC cell proliferation by regulating the TGFβ/PI3K/AKT/GSK3β pathway. The molecular regulatory network of HCC proliferation is improved by this research, which also offers a solid theoretical and experimental foundation for SCUBE3 as a potential new therapeutic target for HCC.

According to previous studies, oxidative stress is a leading cause of dopaminergic neuron death and may contribute to the pathogenesis of Parkinson's disease (PD). In the current study, we used chromatography of gel filtration to identify a novel peptide (Lignosus rhinocerotis peptide [LRP]) from the sclerotium of Lignosus rhinocerotis (Cooke) Ryvarden. Its neuroprotective effect was evaluated using an in vitro PD model constructed by 6‐hydroxydopamine (6‐OHDA)‐stimulated to apoptosis in PC12 cells. The molecular weight of LRP is determined as 1532 Da and the secondary structure is irregular. The simple amino acid sequence of LRP is Thr‐Leu‐Ala‐Pro‐Thr‐Phe‐Leu‐Ser‐Ser‐Leu‐Gly‐Pro‐Cys‐Leu‐Leu. Notably, LRP has the ability to significantly boost the viability of PC12 cells after exposure to 6‐OHDA, as well as enhance the cellular activity of antioxidative enzymes like superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH‐Px). LRP also lowers the level of malondialdehyde (MDA), decreases the activation performance of Caspase‐3, and reduces 6‐OHDA‐induced apoptosis via inhibition of nuclear factor‐kappa B (NF‐κB) activation. These data indicate that LRP may have the potential to act as a neuroprotective agent.