OBJECTIVE:Periplocin, a bioactive component derived from the traditional Chinese medicinal herb Cortex periplocae, has recently emerged as a promising agent for cancer treatment. However, its mode of action, particularly in the context of multiple myeloma (MM), remains poorly characterized. This study investigates the antitumor efficacy of periplocin against MM and elucidates its underlying molecular mechanisms. METHODS:Cell viability was assessed using the cell counting kit-8 assay, while flow cytometry was used to analyze cell cycle distribution and apoptosis rates. The in vivo antitumor effect of periplocin was validated in a murine MM xenograft model. RNA sequencing (RNA-seq) analyses, network pharmacology, molecular docking and cellular thermal shift assay (CETSA) were used to identify potential targets and signaling pathways of periplocin in treating MM. The Gene Expression Profiling database was used to evaluate the correlation between candidate gene expression and survival outcomes in MM patients. A dual-luciferase reporter assay was used to evaluate transcriptional activity, and CUT&Tag polymerase chain reaction (PCR) was used to detect the effect of periplocin on the binding of signal transducer and activator of transcription 3 (STAT3) protein to the Myc proto-oncogene protein (MYC) promoter region. The protein expressions were explored via Western blotting analysis. RESULTS:Periplocin exhibited encouraging anti-MM activity in both cellular and animal models. Periplocin induced MM cell apoptosis and cell cycle blockade. Periplocin prevented the JAK2/STAT3/AKT/mTOR signaling cascade from being activated, impeding MM cell proliferation. Molecular docking and CETSA showed the interaction between periplocin and STAT3. RNA-seq analysis showed that periplocin regulated STAT3-mediated expression of MYC, whose high expression was closely related to poor prognosis in MM. Moreover, the dual-luciferase reporter assay showed that periplocin significantly suppressed STAT3 transcriptional activity. The CUT&Tag PCR results revealed that periplocin effectively inhibited the binding of STAT3 to the MYC promoter DNA region. Periplocin downregulated MYC expression. CONCLUSION:Periplocin targets STAT3, suppressing MYC expression and leading to the inhibition of MM cell proliferation; this highlights its promise as a novel treatment option for MM. Please cite this article as: Wei RF, Chen JX, Lai SP, Chen ZA, Zhou YY, Liao YP, Chen Y. Periplocin targets STAT3 to suppress MYC expression and inhibit multiple myeloma cell proliferation. J Integr Med. 2026; Epub ahead of print.

Stress-induced premature senescence (SIPS) of endothelial cells can cause endothelial dysfunction. As a first-line antidiabetic agent, the specific role of metformin in SIPS has not yet been clarified. In this study, an in vitro SIPS model was induced by exposing human umbilical vein endothelial cells (HUVECs) to hydrogen peroxide (H2O2), and the effects of metformin on cell senescence, proliferation, migration, tube formation, and mitochondrial function were evaluated. Gene expressions altered by metformin were profiled via transcriptome sequencing. Specifically, the potential involvement of migrasome-mediated mitocytosis in metformin-driven effects was examined using confocal microscopy and siRNA-mediated silencing. The results showed that metformin significantly reduced SA-β-gal activity and restored the migration and tube-forming capacities of H2O2-induced senescent HUVECs. Moreover, metformin regulated mitochondrial dynamics, restored mitochondrial membrane potential, and attenuated intracellular oxidative stress. Notably, transcriptomic and functional analyses suggested that metformin enhanced migrasome formation and migrasome-mediated mitocytosis. Inhibition of migrasome formation by siTSPAN4 abolished the protective effect of metformin against SIPS. Collectively, these findings demonstrate that metformin alleviates early SIPS-associated changes in HUVECs and suggest that migrasome-mediated mitocytosis contributes to this protection by ameliorating mitochondrial dysfunction. This provides novel mechanistic insight into the vascular protective effects of metformin.

Chimeric autoantibody receptor T (CAAR-T) cell therapy extends CAR-T technology to target autoreactive immune cells, offering a novel approach for treating autoimmune disorders. In hemophilia A, the development of anti-factor VIII (FVIII) inhibitors poses a major clinical challenge. This study investigates the therapeutic potential of CAAR-T cells engineered with FVIII C1 or A2 domains to eliminate inhibitor-producing B cells. In vitro cytotoxicity assays confirmed that C1 and A2 CAAR-T cells exhibited comparable killing efficiency against their respective targets. In an F8KO hemophilia A mouse model, both CAAR-T cells significantly reduced circulating FVIII inhibitors, while their combination further suppressed inhibitor re-emergence after FVIII rechallenge. In a humanized NCG mouse model, combined CAAR-T therapy effectively inhibited in vivo target cell expansion. These findings demonstrate that CAAR-T therapy, particularly the combinatorial approach, holds promise for addressing FVIII inhibitor formation in hemophilia A, offering a targeted and effective treatment strategy.

Objective To investigate the mechanism by which Sijunzi Decoction inhibits the growth of hepatocellular carcinoma (HCC) by observing its effects on HCC in mice and its influence on retinol dehydrogenase 5 (RDH5), the Hippo/YAP pathway, epithelial-mesenchymal transition (EMT), and stemness maintenance of cancer stem cells (CSCs). MethodsC57BL/6 mice were randomly divided into group A (non-spleen-deficiency HCC with RDH5 overexpression), group B (spleen-deficiency HCC with RDH5 overexpression), group C (spleen-deficiency HCC with empty vector), group D [spleen-deficiency HCC treated with low-dose Sijunzi Decoction, 4.6 g/(kg·d)], and group E [spleen-deficiency HCC treated with high-dose Sijunzi Decoction, 18.2 g/(kg·d)]. A spleen-deficiency model was established using reserpine. RDH5 overexpression or empty-vector transfection was performed using lentiviral transduction, and an orthotopic HCC model was constructed by transplanting Hepa1-6 cells. Groups D and E were administered Sijunzi Decoction by gavage. Tumor volume and weight were measured, pathological changes were observed by hematoxylin-eosin (HE) staining, and the expression of related proteins was detected by western blot. ResultsCompared with group C, tumor volume and weight were reduced in groups B, D, and E (all P ＜ 0.05). Compared with group B, tumor volume and weight were further reduced in groups D and E (all P ＜ 0.05), showing a certain dose-related trend. After intervention with Sijunzi Decoction, RDH5 expression was increased in groups D and E compared with group C (both P ＜ 0.05). Detection of the Hippo/YAP pathway showed that, compared with groups C and B, the expression levels of phosphorylated mammalian sterile 20-like kinase 1 (p-MST1), Salvador family WW domain-containing protein 1 (SAV1), Mps1 binder protein 1 (MOB1), phosphorylated large tumor suppressor 1 (p-LATS1), and phosphorylated Yes-associated protein (p-YAP) were increased in groups D and E, while total YAP protein expression was decreased (all P ＜ 0.05). EMT analysis showed that, compared with groups C and B, epithelial cadherin (E-cadherin) expression was increased in groups D and E, whereas neural cadherin (N-cadherin) and vimentin expression were decreased (all P ＜ 0.05). The expression levels of CSC stemness markers, including Nanog, sex-determining region Y-box 2 (Sox2), octamer-binding transcription factor 4 (Oct-4), and epithelial cell adhesion molecule (EpCAM), were lower in groups D and E than in groups C and B (all P ＜ 0.05). The effects of Hippo/YAP pathway activation, EMT reversal, and inhibition of CSC stemness maintenance were more pronounced in the Sijunzi Decoction intervention groups (groups D and E) than in group B, showing a certain dose-related trend. ConclusionsSijunzi Decoction can effectively inhibit the growth of spleen-deficiency HCC. Its mechanism may be associated with restoration of RDH5 expression, activation of the Hippo/YAP pathway, reversal of EMT, and inhibition of stemness maintenance in HCC CSCs. The anti-HCC effect of Sijunzi Decoction does not depend solely on RDH5 as a single target, but reflects an integrated mode of action involving synergistic regulation by multiple components and multiple targets.

BCL6 is a master regulator of germinal center (GC) B cells. Further identification and characterization of factors that may play a role within the BCL6 network is important for our understanding of GC B cell differentiation and function. Here, through co-Immunoprecipitation coupled with mass spectrometry, we identify CHAF1B as a new partner in the BCL6 complex, which is highly expressed in GC B cells, promoting GC formation and humoral immunity. Loss of CHAF1B impairs the dark zone (DZ) and light zone (LZ) organization and induces apoptosis, resulting in abnormal GC responses and antibody production. Mechanistically, CHAF1B stabilizes BCL6/TBL1XR1 complex to promote GC B cell differentiation by cooperative transcriptional repression. Furthermore, overexpression of CHAF1B in B cells reduces the plasmablast by extending GC reaction, which is positively related to the production of high affinity antibodies in response to vaccines or pathogens. These findings not only advance the understanding of GC biology but also had potential implications for developing targeted strategies to improve vaccination efficacy.

Multiple myeloma (MM) is highly heterogeneous, with relapse occurring in the majority of cases, and recent advancements in single-cell RNA sequencing (scRNA-seq), sc-metabolism profiling, and bulk RNA-seq have facilitated the identification of cell subpopulations and metabolic reprogramming at the single-cell level, uncovering novel molecular mechanisms. This study aims to establish a multi-omics atlas of MM, characterizing the cell subpopulations and signaling pathways that drive immune evasion and disease progression. Additionally, sc-metabolic profiling identifies reprogramming patterns and informs therapeutic screening. We integrated scRNA-seq and bulk RNA-seq data using R to analyze immune and non-immune cell features and pathways in MM. Metabolic reprogramming was assessed via sc-metabolic profiling, and drug candidates were screened through multi-omics integration, with efficacy evaluated in vitro using CCK-8 assays, flow cytometry, Western blotting, and CalcuSyn software. Novel MM subpopulations were identified, including myeloma-activated hematopoietic stem cells and ISG15+ B cells, which correlated with survival and were validated by multiplex immunofluorescence. IFN-γ is primarily secreted by effector memory CD8+T cells, and IFN-α is primarily secreted by non-classical monocytes, driving an IFN-γ/α-B2M feedback loop. Multi-omics identified four drug candidates, each demonstrating anti-tumor effects against myeloma cell lines.

Background: Periplocin, a bioactive compound extracted from Cortex periplocae, has long been employed in traditional medicine for its diverse therapeutic effects, particularly in alleviating inflammation and inhibiting cancer progression. However, despite its potential benefits, the underlying molecular mechanisms of periplocin, especially in the context of leukemia treatment, remain poorly elucidated, warranting further investigation to uncover its precise role and therapeutic targets. Methods: A comprehensive approach combining network pharmacology and transcriptomic analysis was utilized to identify HDAC10 as a critical downstream target of periplocin. Molecular docking and dynamic simulation studies were performed to elucidate the interaction between periplocin and HDAC10 at the molecular level. Additionally, functional assays, including apoptosis induction, cell cycle regulation, and pathway inhibition experiments, were conducted to validate the mechanistic role of HDAC10 and its relevance to periplocin's anti-leukemic effects. Results: Periplocin was identified as an effective inhibitor of HDAC10, binding specifically to its hydrophobic active pocket and suppressing its enzymatic activity. This inhibition disrupted downstream signaling, particularly the NF-κB pathway, leading to significant apoptosis and cell cycle arrest in leukemia cells. These results therapy, offering insights into its mechanism of action through HDAC10 targeting. Conclusion: In conclusion, periplocin, as a novel natural compound, exhibits significant anti-leukemia activity, highlighting its potential as a promising therapeutic candidate for leukemia treatment. The findings contribute to the growing interest in natural compounds as innovative solutions for addressing unmet clinical needs in hematological malignancies.

Introduction: Multiple myeloma (MM) remains incurable despite ongoing advancements in treatment, with the majority of patients eventually relapsing. Although advances in proteasome inhibitors, immunomodulatory drugs, and hematopoietic cell transplantation have improved survival, long-term outcomes remain suboptimal. High-throughput single-cell RNA sequencing (scRNA-seq), bulk RNA-seq, and single-cell metabolic profiling enable unprecedented resolution of tumor microenvironment (TME) heterogeneity and metabolic reprogramming. Here, we integrate the largest multi-omics dataset to date , aiming to: (1) identify novel immune and non-immune cell subpopulations driving immune evasion and disease progression; (2) elucidate key signaling circuits—particularly an IFN-γ/IFN-α–B2M positive feedback loop; and (3) discover targeted metabolic therapies. Methods: We analyzed scRNA-seq data from 113 individuals (healthy controls and MM patients across disease stages; 111,640 cells) alongside bulk RNA-seq from the MMRF cohort and GEO. Cell clustering, annotation, pseudo-time trajectories, ligand-receptor interactions (iTALK), transcription factor networks, and pathway enrichment (GSEA/GSVA) were performed in R. Single-cell metabolic activity was quantified using the scMetabolism R package. CIBERSORTx deconvolution of bulk RNA-seq enabled survival-linked abundance estimates for each cluster. Key subpopulations were validated by multiplex immunofluorescence. In vitro drug screening on MM cells evaluated four metabolic inhibitors-galloflavin (LDHA), CB-839 (GLS1), NAC (OXPHOS), EGCG (multi-target)-and two combination regimens (galloflavin+NAC, CB-839+EGCG) via CCK-8 proliferation assays, flow cytometry, Western blot, and CalcuSyn synergy analysis. A retrospective clinical cohort assessed serum IFN-γ, IL-6, CRP, β2-microglobulin, ferritin, iron, transferrin, and TSAT levels. Results: We defined 23 plasma cell clusters and diverse non-plasma subsets (including HSCs, erythroid progenitors, erythroblasts, macrophages, T and B cell subsets, and CAFs). Relapsed cases were enriched for exhausted T cells, γδ T cells, fibroblast progenitor cells (FPCs), and myeloid-erythroid progenitor cells (MEPCs), all of which correlated with inferior prognosis. Two novel bone marrow subpopulations-ISG15⁺ B cells and LYZ⁺KIT⁺ erythroid progenitors (MEPCs)-expressed immune checkpoint molecules, were survival-associated, and participated in an IFN-γ/IFN-α-B2M positive feedback loop. Cell–cell communication analysis revealed predominant B2M–TFRC signaling and upregulation of KRAS, IL6-JAK-STAT3, MYC, IFN-γ, and IFN-α pathways. IFN-γ from effector memory CD8⁺ T cells and IFN-α from non-classical monocytes established the IFN-γ/IFN-α–B2M feedback circuit via ISGF3-mediated upregulation of B2M and TFRC, sustaining downstream STAT, MYC, and anti-apoptotic signaling. Chronic, sustained, and excessive activation of the IFN-α signaling pathway may also contribute to T cell exhaustion. Metabolic profiling showed malignant plasma cells exhibited increased glycolysis, oxidative phosphorylation (OXPHOS), and glutamine metabolism, with overexpression of LDHA, GLS1, and related enzymes. All four agents suppressed MM cell proliferation; the CB-839+EGCG combination demonstrated strong synergy (CI <1), induced G2/M arrest, enhanced apoptosis (↑Bax/Bcl-2 ratio), and markedly inhibited proliferation. Clinical specimens confirmed elevated IFN-γ, IL-6, CRP, β2-microglobulin, and ferritin, alongside reduced serum iron, transferrin, and TSAT in MM patients. Conclusion: This multi-omics study delineates the complex cellular architecture of the MM TME, uncovers a novel IFN-γ/IFN-α–B2M positive feedback loop central to immune evasion and disease progression, and identifies CB-839+EGCG as a promising metabolic therapy. Our atlas provides a comprehensive resource for elucidating MM pathogenesis and tailoring targeted immunometabolic interventions.

Acetaminophen (APAP) stands as the predominant contributor to drug-induced liver injury (DILI), and limited options are available. β-Arrestin1 (ARRB1) is involved in numerous liver diseases. However, the role of ARRB1 in APAP-induced liver injury remained uncertain. Wild-type (WT) and ARRB1 knockout (KO) mice were injected with APAP and sacrificed at the indicated times. The histological changes, inflammation, endoplasmic reticulum (ER) stress, and apoptosis were then evaluated. Hepatic cell lines AML-12 and primary hepatocytes were used for in vitro analyses. Systemic ARRB1 -KO mice were susceptible to APAP-induced hepatotoxicity, as indicated by larger areas of centrilobular necrosis area and higher levels of ALT, AST, and inflammation level. Moreover, ARRB1 -KO mice exhibited increased ER stress (indicated by phosphorylated α subunit of eukaryotic initiation factor 2 (p-eIF2α)-activating transcription factor 4 (ATF4)-CCAAT-enhancer-binding protein homologous protein (CHOP)) and apoptosis (indicated by cleaved caspase 3). Further rescue experiments demonstrated that the induction of apoptosis was partially mediated by ER stress. Overexpression of ARRB1 alleviated APAP-induced ER stress and apoptosis. Moreover, co-IP analysis revealed that ARRB1 directly bound to p-eIF2α and eIF2α. ARRB1 protected against APAP-induced hepatoxicity through targeting ER stress and apoptosis. ARRB1 is a prospective target for treating APAP-induced DILI. Graphical Abstract ARRB1 mitigates APAP-induced hepatotoxicity through regulating ER stress (p-eIF2α-ATF4-CHOP) and apoptosis (p-JNK and cleaved caspase 3) via binding to p-eIF-2α

This report describes a case of concomitant diabetic ketoacidosis (DKA) and thyroid storm (TS) in a 20-year-old male patient that presented both diagnostic and management challenges owing to their intricate interrelationship in endocrine-metabolic disorders. The patient, previously diagnosed with type 1 diabetes mellitus (T1DM) and hyperthyroidism, was admitted to the emergency department with symptoms of DKA and progressive exacerbation of TS. Initial treatment focused on correcting DKA; as the disease progressed to TS, it was promptly recognized and treated. This case emphasizes the rarity of simultaneous occurrence of DKA and TS, as well as the challenges in clinical diagnosis posed by the interacting pathophysiological processes and overlapping clinical manifestations of DKA and TS. The patient’s treatment process involved multiple disciplines, and after treatment, the patient’s critical condition of both endocrine metabolic diseases was alleviated, after which he recovered and was eventually discharged from the hospital. This case report aims to emphasize the need for heightened awareness in patients with complex clinical presentations, stress the possibility of concurrent complications, and underscore the importance of prompt and collaborative treatment strategies.

Background: Multiple myeloma (MM) is characterized by destructive osteolytic lesions, hypercalcemia, renal insufficiency, and anemia. However, bortezomib (Btz) has been recognized as a cornerstone treatment for various types of MM. Therefore, this study explored the effect of erastin on the efficacy of Btz and evaluated the synergistic effects of erastin in combination with Btz on MM cells. Methods: Glutathione (GSH) level was evaluated in MM cell lines to determine its effects on redox balance and cell growth. Furthermore, Solute Carrier Family 7 Member 11 (SLC7A11) was inhibited in MM cells using small-interfering RNA (siRNA) and erastin to determine its effect of redox balance on cell proliferation. Moreover, western blot analysis, flow cytometry, and ferroptosis-related verification experiments were employed to assess the changes that occur after treatment in the cell cycle, the expression of DNA damage repair marker protein, and ferroptosis. Additionally, the synergistic zero interaction potency (ZIP) scores and combination indexes (CIs) of these two drugs were calculated using different concentrations of Btz and erastin, and MM cell proliferation was compared when treated with single and combined drugs. Results: It was observed that increased GSH levels (p < 0.05) disrupted the redox equilibrium and promoted MM cell proliferation. Moreover, activation of siSLC7A11 induced the Ataxia Telangiectasia and Rad3-related Checkpoint Kinase 1 (ATR-CHK1) DNA repair pathway, resulting in a decrease in GSH levels (p < 0.05), a rise in intracellular reactive oxygen species (ROS) levels, alterations in intracellular redox equilibrium, and the induction of ferroptosis. Additionally, the ATR-CHK1 DNA repair pathway resulted in cell cycle S-phase arrest and effectively reduced MM cell growth. However, inhibiting SLC7A11 (p < 0.05) led to higher MM cell response to Btz. Moreover, the combination of erastin and Btz significantly increased cytotoxicity in MM cells (p < 0.05). Conclusion: Erastin increases the level of reactive oxygen species (ROS) in MM cells by inhibiting SLC7A11, which activates the ATR-CHK1 DNA damage repair pathway and causes MM cells to ferroptosis. Furthermore, erastin synergistically increases the cytotoxicity of Btz in multiple myeloma.

Multiple myeloma (MM) is closely related to abnormal RNA splicing in its pathogenesis. CDC2-like kinase-2 (CLK2) regulates RNA splicing by phosphorylating serine/arginine-rich splicing factors (SRSFs), but the role of CLK2 in MM remains undefined. This study was to explore the role and mechanism of CLK2 in MM. Analyzing GEO datasets of MM patients found that high CLK2 expression predicted poor prognosis. Overexpression of CLK2 promoted the cell proliferation and cell cycle progression of MM cell ARP1 and H929. Knockdown or inhibition of CLK2 suppressed cell proliferation and induced cell apoptosis and cell cycle arrest in ARP1 and H929 cells in vitro. An MM xenograft tumor experiment showed that CLK2 overexpression promoted tumor growth, while CLK2 inhibition suppressed tumor growth in vivo. Mechanistic studies revealed that interfering CLK2 inhibited SRSF phosphorylation, and induced exon 9 skipping of RAE1, resulting in nonsense-mediated mRNA decay (NMD) of RAE1. In addition, RAE1 knockdown inhibited cell proliferation in ARP1 and H929 cells. Moreover, RAE1 overexpression promoted cell proliferation and cell cycle progression of ARP1 and H929 cells, and partially reversed the antitumor effect of CLK2 knockdown. Targeting CLK2 shows antitumor effects on MM partially through inhibiting SRSF phosphorylation and inducing NMD of RAE1. Therefore, targeting the CLK2/SRSFs/RAE1 axis could be a potential therapeutic strategy for MM.

Background: The myeloproliferative neoplasm (MPN) is a heterogeneous group of clonal hyperplasia hematopoietic stem cell disorders, predominantly affecting middle-aged and elderly individuals, with a slow disease progression. With advancements in disease-related research, the survival rates of MPN patients have significantly improved. This research primarily focuses on cardiovascular disease mortality (CVM) and prognostic factors in MPN patients, aiming to provide clinicians with more comprehensive references. Methods: A total of 24,277 patients were included in the Surveillance, Epidemiology, and End Results (SEER) database. Cumulative mortality was assessed using a competing risk model, univariate and multivariate regression analysis of cardiovascular disease (CVD) mortality risk factors, and a comparison of standardized mortality ratio (SMR) and general population CVM. Results: Among the 24,277 patients included in this study, a total of 8841 deaths occurred during the follow-up period, with 2429 attributed to CVD. Notably, the risk of CVM was found to be significantly higher in patients with MPNs compared to the general population. Furthermore, this risk increased over time. CVD emerged as the predominant cause of death among individuals aged over 80 years and younger patients exhibited a significantly elevated SMR. Additionally, age, race, marital status, and insurance status were identified as independent prognostic factors for CVM. Conclusion: The incidence of cardiovascular events in patients with MPNs is significantly higher compared to the general population. Early screening and assessment of cardiac health should be implemented in MPN patients to prevent the occurrence of cardiovascular events and enhance their prognosis.

IntroductionAdamantinomatous craniopharyngioma (ACP) is difficult to cure completely and prone to recurrence after surgery. Ferroptosis as an iron-dependent programmed cell death, may be a critical process in ACP. The study aimed to screen diagnostic markers related to ferroptosis in ACP to improve diagnostic accuracy.MethodsGene expression profiles of ACP were obtained from the gene expression omnibus (GEO) database. Limma package was used to analyze the differently expressed genes (DEGs). The intersection of DEGs and ferroptosis-related factors was obtained as differently expressed ferroptosis-related genes (DEFRGs). Enrichment analysis was processed, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), disease ontology (DO), gene set enrichment analysis (GSEA), and Gene Set Variation Analysis (GSVA) analysis. Machine learning algorithms were undertaken for screening diagnostic markers associated with ferroptosis in ACP. The levels of DEFRGs were verified in ACP patients. A nomogram was drawn to predict the relationship between key DEFRG expression and risk of disease. The disease groups were then clustered by consensus clustering analysis.ResultsDEGs were screened between ACP and normal samples. Ferroptosis-related factors were obtained from the FerrDb V2 and GeneCard databases. The correlation between DEFRGs and ferroptosis markers was also confirmed. A total of 6 overlapped DEFRGs were obtained. Based on the results of the nomogram, CASP8, KRT16, KRT19, and TP63 were the protective factors of the risk of disease, while GOT1 and TFAP2C were the risk factors. According to screened DEFRGs, the consensus clustering matrix was differentiated, and the number of clusters was stable. CASP8, KRT16, KRT19, and TP63, were upregulated in ACP patients, while GOT1 was downregulated. CASP8, KRT16, KRT19, TP63, CASP8, and GOT1 affect multiple ferroptosis marker genes. The combination of these genes might be the biomarker for ACP diagnosis via participating ferroptosis process.DiscussionFerroptosis-related genes, including CASP8, KRT16, KRT19, TP63, and GOT1 were the potential markers for ACP, which lays the theoretical foundation for ACP diagnosis.

IntroductionEarly stable deep molecular response (DMR) to nilotinib is associated with goal of treatment-free remission (TFR) in patients with chronic-phase chronic myeloid leukemia (CML-CP). It is important to early distinguish between patients who can achieve a DMR and those who are fit for TFR.MethodsWe performed a multicenter study to explore the early cumulative MR4.5 rate at 18 months with nilotinib in patients with newly diagnosed CML-CP (ND-CML-CP) in China. Of the 29 institutes, 106 patients with ND-CML-CP received nilotinib (300 mg BID).Results and discussionThe cumulative MR4.5 rate of nilotinib treatment at 18 months was 69.8% (74/106). The cumulative MMR and MR4.0 rates for nilotinib at 18 months were 94.3% (100/106) and 84.9% (90/106), respectively. Patients with an ultra-early molecular response (u-EMR) at 6 weeks were not significantly different in obtaining DMR or MMR by 24 months compared with those without u-EMR (p = 0.7584 and p = 0.9543, respectively). Our study demonstrated that nilotinib treatment in patients with ND-CML-CP contributed to obtain high early MR4.5.

Objective: Multiple myeloma (MM) is an incurable haematological cancer characterized by abnormal proliferation of plasma cells. The promising therapeutic effect of selective inhibitors of nuclear export in MM reveals the broad therapeutic prospects of nuclear localization intervention. Sterol regulatory element binding protein 2 (SREBP2) is a lipid regulatory molecule that has been implicated in the effect of drug therapy for MM. SREBP2 has been reported to be regulated by the antimalarial drug artesunate (ART) through alteration of its nuclear localization and has been shown to inhibit ferroptosis in other tumours. However, the mechanism through which this might occur has not been clarified in MM. Our study aimed to explore whether ART can induce ferroptosis in MM through nuclear localization of SREBP2. Methods: To evaluate whether ferroptosis is induced by treatment with ART in myeloma, we used two types of myeloma cell lines. We first used a series of molecular approaches and other techniques to investigate the impact of ART on cell growth, production of reactive oxygen species (ROS), Fe2+ levels, lipid peroxidation and expression of genes related to ferroptosis. Then, we further explored the mechanism through which ferroptosis may occur in these cells and the relationship between ferroptosis and the nuclear localization of SREBP2. Results: Upregulation of ROS, Fe2+, and lipid peroxidation as well as inhibition of cell growth were observed in myeloma cells after treatment with ART. Expression of acyl CoA synthase long chain family member 4 (ACSL4) was increased, while glutathione peroxidase 4 (GPX4) expression was reduced in cells treated with ART. ART-induced cell death could be reversed by ferropstatin-1 (Fer-1) and deferoxamine mesylate (DFO). Nuclear localization of SREBP2 in myeloma cells was inhibited, accompanied by downregulation of isopentenyl pyrophosphate (IPP) and GPX4, after treatment with ART. Conclusion: In conclusion, our study demonstrated that the antimalarial drug ART can inhibit nuclear localization of SREBP2, downregulate IPP and GPX4, and eventually trigger ferroptosis in myeloma cells. Through this study, we hope to establish a correlation between nuclear localization pathways and mediation of ferroptosis in myeloma cells and provide an innovative direction for exploration-related therapy.

ObjectiveTo evaluate the predictive value of tumor regression grade assessed by MRI (mr-TRG) after neoadjuvant chemoradiotherapy (neo-CRT) for postoperative pathological TRG (pTRG) and prognosis in patients with locally advanced rectal adenocarcinoma (LARC).Materials and methodsThis was a retrospective study from a single center experience. The patients who were diagnosed with LARC and received neo-CRT in our department between January 2016 and July 2021 were enrolled. The agreement between mrTRG and pTRG was assessed with the weighted κ test. Overall survival (OS), progress-free survival (PFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were calculated by Kaplan-Meier analysis and log-rank test.ResultsFrom January 2016 to July 2021, 121 LARC patients received neo-CRT in our department. Among them, 54 patients had complete clinical data, including MRI of pre- and post-neo-CRT, postoperative tumor samples, and follow-up. The median follow-up time was 34.6 months (range: 4.4-70.6 months). The estimated 3-year OS, PFS, LRFS and DMFS were 78.5%, 70.7%, 89.0%, and 75.2%, respectively. The median time from the completion of neo-CRT to preoperative MRI and surgery was 7.1 weeks and 9.7 weeks, respectively. Out of 54 patients, 5 patients achieved mrTRG1 (9.3%), 37 achieved mrTRG2 (68.5%), 8 achieved mrTRG3 (14.8%), 4 achieved mrTRG4 (7.4%), and no patient achieved mrTRG5 after neo-CRT. Regarding pTRG, 12 patients achieved pTRG0 (22.2%), 10 achieved pTRG1 (18.5%), 26 achieved pTRG2 (48.1%), and 6 achieved pTRG3 (11.1%). The agreement between three-tier mrTRG (mrTRG1 vs. mrTRG2-3 vs. mrTRG4-5) and pTRG (pTRG0 vs. pTRG1-2 vs. pTRG3) was fair (weighted kappa=0.287). In a dichotomous classification, the agreement between mrTRG(mrTRG1 vs. mrTRG2-5)and pTRG(pTRG0 vs. pTRG1-3) also resulted in fair agreement (weighted kappa=0.391). The sensitivity, specificity, positive, and negative predictive values of favorable mrTRG (mrTRG 1-2) for pathological complete response (PCR) were 75.0%, 21.4%, 21.4%, and 75.0%, respectively. In univariate analysis, favorable mrTRG (mrTRG1-2) and downstaging N were significantly associated with better OS, while favorable mrTRG (mrTRG1-2), downstaging T, and downstaging N were significantly associated with superior PFS (p<0.05). In multivariate analysis, downstaging N was an independent prognostic factor for OS. Meanwhile, downstaging T and downstaging N remained independent prognostic factors for PFS.ConclusionsAlthough the consistency between mrTRG and pTRG is only fair, favorable mrTRG after neo-CRT may be used as a potential prognostic factor for LARC patients.

Dear Editor, Overwhelming evidence suggests that age itself is a prominent risk factor for COVID-19 morbidity and mortality.1,2 However,the molecular basis of aging's effect on SARS-CoV-2 susceptibility and COVID-19 severity in adults is still not fully understood.Thus,we hypothesized that aging-related cellular landscape alterations influence clinical manifestations,which is critical for determining likely intervention targets to slow the transmission of COVID-19 and reduce severe symptoms.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and has a poor prognosis. Pituitary tumor transforming gene 1 (PTTG1) is highly expressed in HCC, sug-gesting it could play an important role in hepatocellular carcino-genesis. Here, we evaluated the impact of PTTG1 deficiency on HCC development using a diethylnitrosamine (DEN)-induced HCC mouse model and a hepatitis B virus (HBV) regulatory X protein (HBx)-induced spontaneous HCC mouse model. PTTG1 deficiency significantly suppressed DEN-and HBx-induced hepa-tocellular carcinogenesis. Mechanistically, PTTG1 promoted asparagine synthetase (ASNS) transcription by binding to its promoter, and asparagine (Asn) levels were correspondingly increased. The elevated levels of Asn subsequently activated the mTOR pathway to facilitate HCC progression. In addition, aspar-aginase treatment reversed the proliferation induced by PTTG1 overexpression. Furthermore, HBx promoted ASNS and Asn metabolism by upregulating PTTG1 expression. Overall, PTTG1 is involved in the reprogramming of Asn metabolism to promote HCC progression and may serve as a therapeutic and diagnostic target for HCC.Significance: PTTG1 is upregulated in hepatocellular carcinoma and increases asparagine production to stimulate mTOR activity and promote tumor progression.