OBJECTIVE To investigate the mechanism of pachymic acid on renal injury in pregnancy induced hypertension （PIH） rats by regulating the silent information regulator transcript 1/peroxisome proliferator-activated receptor γ coactivator-1α （Sirt1/PGC-1α） pathway. METHODS Pregnant SD rats were prepared by co-caging and PIH model was induced using N-nitro-L- arginine methyl ester （L-NAME） method. PIH rats were randomly divided into model group， L-pachymic acid （low-dose pachymic acid， 10 mg/kg） group， H-pachymic acid （high-dose pachymic acid， 20 mg/kg） group， and H-pachymic acid+EX527 （20 mg/kg pachymic acid+10 mg/kg EX527） group， with 6 rats in each group. Another 6 normal pregnant rats were selected as blank group. Each group was given relevant medicine or solvent intragastrically or intraperitoneally daily， once a day， for 28 consecutive days. After the last administration， 24 h urinary protein and tail artery systolic blood pressure （SBP） were measured in pregnant rats from each group， along with the levels of serum creatinine （Scr）， blood urea nitrogen （BUN），uric acid （UA）， and cystatin C （Cys-C）. The contents of superoxide dismutase （SOD）， malondialdehyde （MDA）， glutathione peroxidase （GSH-Px）， and 8-hydroxy-2′-deoxyguanosine （8-OHdG） in renal tissue， as well as the mRNA and protein expression levels of Sirt1 and PGC-1α， were also determined. Meanwhile， renal histopathological changes in rats from each group were evaluated using hematoxylin-eosin （HE） staining and periodic acid-Schiff （PAS） staining. RESULTS Compared with model group， L-pachymic acid group and H-pachymic acid group exhibited significant decreases in 24 h urine protein quantification， tail artery SBP， Scr， BUN， UA， Cys-C levels， glomerulosclerosis index score of renal tissue， renal tubular injury score， the percentage of PAS positive area， MDA and 8-OHdG （P＜0.05）. Conversely， the contents of SOD and GSH-Px， along with the mRNA and protein expression levels of Sirt1 and PGC-1α， were significantly increased （P＜0.05）. Moreover， these improvements were more pronounced in H-pachymic acid group （P＜0.05）. Compared with H-pachymic acid group， the aforementioned indicators in pregnant rats from the H-pachymic acid+EX527 group showed significant reversal （P＜0.05）. CONCLUSIONS Pachymic acid significantly ameliorates renal injury induced by PIH in rats， potentially through activation of the Sirt1/PGC-1α pathway.

Oral squamous cell carcinoma (OSCC) is a common head and neck malignancy. Approximately 50% to 60% of patients with OSCC are diagnosed at a locally advanced stage (clinical staging III-IVa). Even with comprehensive and sequential treatment primarily based on surgery, the 5-year overall survival rate remains below 50%, and patients often suffer from postoperative functional impairments such as difficulties with speaking and swallowing. Programmed death receptor-1 (PD-1) inhibitors are increasingly used in the neoadjuvant treatment of locally advanced OSCC and have shown encouraging efficacy. However, clinical practice still faces key challenges, including the definition of indications, optimization of combination regimens, and standards for efficacy evaluation. Based on the latest research advances worldwide and the clinical experience of the expert group, this expert consensus systematically evaluates the application of PD-1 inhibitors in the neoadjuvant treatment of locally advanced OSCC, covering combination strategies, treatment cycles and surgical timing, efficacy assessment, use of biomarkers, management of special populations and immune related adverse events, principles for immunotherapy rechallenge, and function preservation strategies. After multiple rounds of panel discussion and through anonymous voting using the Delphi method, the following consensus statements have been formulated: 1) Neoadjuvant therapy with PD-1 inhibitors can be used preoperatively in patients with locally advanced OSCC. The preferred regimen is a PD-1 inhibitor combined with platinum based chemotherapy, administered for 2-3 cycles. 2) During the efficacy evaluation of neoadjuvant therapy, radiographic assessment should follow the dual criteria of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune RECIST (iRECIST). After surgery, systematic pathological evaluation of both the primary lesion and regional lymph nodes is required. For combination chemotherapy regimens, PD-L1 expression and combined positive score need not be used as mandatory inclusion or exclusion criteria. 3) For special populations such as the elderly (≥ 70 years), individuals with stable HIV viral load, and carriers of chronic HBV/HCV, PD-1 inhibitors may be used cautiously under the guidance of a multidisciplinary team (MDT), with close monitoring for adverse events. 4) For patients with a poor response to neoadjuvant therapy, continuation of the original treatment regimen is not recommended; the subsequent treatment plan should be adjusted promptly after MDT assessment. Organ transplant recipients and patients with active autoimmune diseases are not recommended to receive neoadjuvant PD-1 inhibitor therapy due to the high risk of immune related activation. Rechallenge is generally not advised for patients who have experienced high risk immune related adverse events such as immune mediated myocarditis, neurotoxicity, or pneumonitis. 5) For patients with a good pathological response, individualized de escalation surgery and function preservation strategies can be explored. This consensus aims to promote the standardized, safe, and precise application of neoadjuvant PD-1 inhibitor strategies in the management of locally advanced OSCC patients.

ObjectiveTo evaluate the therapeutic effect of Huazhuo SanJie Chubi presciption （HSCD） on chronic gouty arthritis （CGA） rats with low-grade inflammation and to explore the underlying mechanism with a focus on macrophage polarization. MethodsThe 41 male 6-week-old SD rats were randomly allocated， using the random number table， to a normal group （n=8） and a model group （n =33）. CGA with low-grade inflammation was induced in the model group by daily gavage of potassium oxonate （250 mg·kg^-1·d^-1） and hypoxanthine （300 mg·kg^-1·d^-1）， combined with intra-articular injection of a monosodium urate （MSU） crystal suspension （50 μL， 25 g·L^-¹） into the left ankle twice weekly. After 4 weeks of modeling， 3 rats were randomly selected from each group for model validation. The remaining successfully modeled rats were randomly divided into a model group， an HSCD group （10.35 g·kg^-1·d^-1， gavage once daily）， an M1 polarization agonist group （L-methionine sulfoximine， 300 mg·kg^-1， subcutaneous injection every other day）， an M1 polarization agonist + HSCD group， an M2 polarization inhibitor group （PD0325901， 10 mg·kg^-1·d^-1， gavage once daily）， and M2 polarization inhibitor + HSCD group. The corresponding drug or drug combination was administered according to group assignment， whereas rats in the normal and model groups received 0.5% carboxymethyl cellulose sodium （CMC-Na） vehicle （10.35 g·kg^-1·d^-1， gavage once daily）. All interventions were continued for four weeks. During the intervention period， except for the normal group， potassium oxonate （250 mg·kg⁻¹） and hypoxanthine （300 mg·kg^-1） were co-administered by gavage every other day to maintain the model. At the end of treatment， serum uric acid （SUA）， ankle joint diameter and joint swelling index were measured. The levels of high-sensitivity C-reactive protein （hs-CRP）， interleukin-1β （IL-1β）， interleukin-6 （IL-6）， tumor necrosis factor-α （TNF-α）， chemokine C-C motif ligand 2 （CCL2）， S100 calcium-binding protein A8/A9 （S100A8/A9）， interleukin-10 （IL-10） and arginase-1 （Arg-1） in serum and joint fluid were determined by enzyme-linked immunosorbent assay （ELISA）. High-frequency ultrasound was used to assess MSU deposition in the ankle joint. Hematoxylin-eosin （HE） staining was performed to evaluate synovial histopathological changes. Quantitative Real-time PCR and immunofluorescence were used to detect the mRNA and protein expression of the M1 macrophage polarization markers inducible nitric oxide synthase （iNOS） and the M2 macrophage polarization marker scavenger receptor cysteine-rich type 1 protein M130 （CD163） in synovial tissue. ResultsCompared with the normal group， the model group showed significantly elevated SUA level and joint swelling index， and increased levels of pro-inflammatory cytokines， CCL2， and S100A8/A9 in both serum and joint fluid （P<0.05）， accompanied by MSU deposition and synovial inflammation in the ankle joint. The mRNA and protein expression levels of macrophage polarization M1/M2 markers iNOS and CD163 in synovial tissues were also significantly up-regulated （P<0.05）. Compared with model group， rats in HSCD group had significantly lower SUA levels， attenuated joint swelling， reduced serum levels of pro-inflammatory cytokines， and decreased levels of CCL2 and S100A8/A9 in both serum and joint fluid， accompanied with alleviated MSU deposition and synovial inflammation （P<0.05）. HSCD markedly downregulated the mRNA and protein expression of M1 marker iNOS （P<0.05）， whereas it had no significant effect on the expression of M2 marker CD163. Compared with the M1 polarization agonist group， the M1 polarization agonist + HSCD group showed significantly reduced joint swelling， lower serum levels of pro-inflammatory cytokines， and decreased levels of CCL2 and S100A8/A9 in joint fluid （P<0.05）. In addition， synovial inflammatory cell infiltration and angiogenesis were attenuated， and iNOS mRNA and protein expression levels were significantly reduced （P<0.05）. Compared with the M2 polarization inhibitor group， the M2 polarization inhibitor + HSCD group exhibited reduced joint swelling， decreased levels of CCL2 and S100A8/A9 in joint fluid and ameliorated synovial inflammation （P<0.05）， whereas the levels of anti-inflammatory mediators （IL-10， Arg-1） and CD163 mRNA and protein expression were not significantly increased. ConclusionHSCD alleviates low-grade inflammation in CGA rats， at least in part， by inhibiting macrophage polarization toward the M1 phenotype.

Intervertebral disc degeneration (IVDD) is the predominant pathological contributor to chronic low back pain, a pervasive musculoskeletal condition affecting over 630 million people globally and imposing tremendous socioeconomic and public health burdens. The etiopathogenesis of IVDD is remarkably complex and multifactorial, involving intricate crosstalk among chronic inflammatory responses, extracellular matrix (ECM) catabolism, cellular senescence, aberrant programmed cell death (including apoptosis, pyroptosis, and ferroptosis), mitochondrial dysfunction, and oxidative damage. Compelling evidence indicates that the inflammatory microenvironment acts as a decisive driving force throughout the entire degenerative course of IVDD. Among the diverse inflammatory mediators, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) serve as core pro-inflammatory cytokines that initiate and perpetuate the degenerative cascade. These two pivotal cytokines collectively activate an array of canonical intracellular signaling pathways, including nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 (NLRP3) inflammasome, and the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) cascade. Such interconnected signaling networks trigger a self-reinforcing positive feedback loop, which exacerbates inflammatory reactions, disrupts the anabolic-catabolic homeostasis of the ECM, promotes oxidative stress and mitochondrial injury, induces multiple forms of disc cell death, and ultimately leads to progressive structural collapse and functional deterioration of the intervertebral disc. Conventional therapeutic strategies, dominated by nonsteroidal anti-inflammatory drugs and surgical interventions, are limited by systemic adverse reactions, suboptimal long-term efficacy, and the risk of adjacent segment degeneration. In contrast, traditional Chinese medicine (TCM) exhibits prominent advantages in the prevention and treatment of IVDD by virtue of its holistic regulation, syndrome differentiation, and multi-component, multi-target, multi-pathway pharmacological properties. This review systematically elucidates the molecular mechanisms by which inflammation-associated signaling pathways modulate disc cell fate and ECM metabolic homeostasis, and comprehensively summarizes the experimental progress over the past five years on TCM monomers and compound formulas for intervening in IVDD. Accumulating studies have confirmed that numerous natural active ingredients isolated from herbal medicines (ferulic acid, mangiferin, paeonol, astragaloside IV) and representative TCM compound prescriptions (Bushen Huoxue Formula, Shensuitongzhi Formula, Fuzi Decoction) exert synergistic protective effects by coordinately targeting core signaling hubs. These TCM agents demonstrate potent anti-inflammatory, antioxidant, anti-apoptotic, anti-pyroptotic, anti-ferroptotic, ECM-protective, and autophagy-regulating bioactivities, thereby effectively decelerating the pathological progression of IVDD. Despite remarkable progress, current investigations are still confronted by several critical limitations. Most studies are restricted to validating the regulatory effects of single TCM components on individual signaling pathways, leaving the systematic, dynamic, and synergistic mechanisms of TCM compound formulas within multi-pathway regulatory networks largely unexplored. Furthermore, clinical translation of TCM is severely hampered by the lack of efficient targeted drug delivery systems, unclear pharmacokinetic profiles, suboptimal local bioavailability, and incomplete long-term safety assessments. Therefore, future research should adopt an interdisciplinary paradigm integrating multi-omics technologies, artificial intelligence, organoid models, and organ-on-chip systems to systematically decipher the scientific basis of TCM against IVDD. Concurrently, the development of intelligent, site-specific delivery systems (hydrogels, nanoparticles, exosome-based carriers) is urgently needed to enhance the local accumulation and sustained release of TCM ingredients. By deepening mechanistic exploration and accelerating translational research, TCM is expected to evolve into safe, effective, and personalized precision therapeutic regimens for IVDD, offering novel and reliable solutions for the clinical management of chronic low back pain.

Intervertebral disc degeneration (IVDD) is the predominant pathological contributor to chronic low back pain, a pervasive musculoskeletal condition affecting over 630 million people globally and imposing tremendous socioeconomic and public health burdens. The etiopathogenesis of IVDD is remarkably complex and multifactorial, involving intricate crosstalk among chronic inflammatory responses, extracellular matrix (ECM) catabolism, cellular senescence, aberrant programmed cell death (including apoptosis, pyroptosis, and ferroptosis), mitochondrial dysfunction, and oxidative damage. Compelling evidence indicates that the inflammatory microenvironment acts as a decisive driving force throughout the entire degenerative course of IVDD. Among the diverse inflammatory mediators, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) serve as core pro-inflammatory cytokines that initiate and perpetuate the degenerative cascade. These two pivotal cytokines collectively activate an array of canonical intracellular signaling pathways, including nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3 (NLRP3) inflammasome, and the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) cascade. Such interconnected signaling networks trigger a self-reinforcing positive feedback loop, which exacerbates inflammatory reactions, disrupts the anabolic-catabolic homeostasis of the ECM, promotes oxidative stress and mitochondrial injury, induces multiple forms of disc cell death, and ultimately leads to progressive structural collapse and functional deterioration of the intervertebral disc. Conventional therapeutic strategies, dominated by nonsteroidal anti-inflammatory drugs and surgical interventions, are limited by systemic adverse reactions, suboptimal long-term efficacy, and the risk of adjacent segment degeneration. In contrast, traditional Chinese medicine (TCM) exhibits prominent advantages in the prevention and treatment of IVDD by virtue of its holistic regulation, syndrome differentiation, and multi-component, multi-target, multi-pathway pharmacological properties. This review systematically elucidates the molecular mechanisms by which inflammation-associated signaling pathways modulate disc cell fate and ECM metabolic homeostasis, and comprehensively summarizes the experimental progress over the past five years on TCM monomers and compound formulas for intervening in IVDD. Accumulating studies have confirmed that numerous natural active ingredients isolated from herbal medicines (ferulic acid, mangiferin, paeonol, astragaloside IV) and representative TCM compound prescriptions (Bushen Huoxue Formula, Shensuitongzhi Formula, Fuzi Decoction) exert synergistic protective effects by coordinately targeting core signaling hubs. These TCM agents demonstrate potent anti-inflammatory, antioxidant, anti-apoptotic, anti-pyroptotic, anti-ferroptotic, ECM-protective, and autophagy-regulating bioactivities, thereby effectively decelerating the pathological progression of IVDD. Despite remarkable progress, current investigations are still confronted by several critical limitations. Most studies are restricted to validating the regulatory effects of single TCM components on individual signaling pathways, leaving the systematic, dynamic, and synergistic mechanisms of TCM compound formulas within multi-pathway regulatory networks largely unexplored. Furthermore, clinical translation of TCM is severely hampered by the lack of efficient targeted drug delivery systems, unclear pharmacokinetic profiles, suboptimal local bioavailability, and incomplete long-term safety assessments. Therefore, future research should adopt an interdisciplinary paradigm integrating multi-omics technologies, artificial intelligence, organoid models, and organ-on-chip systems to systematically decipher the scientific basis of TCM against IVDD. Concurrently, the development of intelligent, site-specific delivery systems (hydrogels, nanoparticles, exosome-based carriers) is urgently needed to enhance the local accumulation and sustained release of TCM ingredients. By deepening mechanistic exploration and accelerating translational research, TCM is expected to evolve into safe, effective, and personalized precision therapeutic regimens for IVDD, offering novel and reliable solutions for the clinical management of chronic low back pain.

Background/Aims: Liver transplantation (LT) following total hepatectomy is a life-saving treatment for hepatocellular carcinoma (HCC). The HCC recurrence after LT hinders the effectiveness of the procedure. The objective of this study is to develop a pre-operative risk stratification model based on a liquid biopsy. Methods: We conducted a comprehensive multi-omics study of 260 HCC patients from three centers, including clinical data, low-coverage whole-genome sequencing of cell-free DNA (cfDNA) from plasma, as well as whole-exome, single-nucleus RNA, and spatial transcriptomics from matched tumor and non-tumor tissues. Results: We identified cfDNA-derived copy number alteration (CNA) signatures associated with post-transplant recurrence. By integrating cfDNA-derived CNA profiles with single-cell transcriptomic data, we traced recurrence-associated cfDNA to a distinct subpopulation of malignant cells within the primary tumor. These cells were embedded in a pro-metastatic microenvironment of specialized endothelial subtypes and cancer-associated fibroblasts. Notably, most recurrence-associated lesions were detectable in cfDNA prior to liver transplantation (LT). Building on these insights, we developed the ZJU Criteria based on CNA fragments and tumor markers, a pre-LT risk prediction tool that integrates conventional clinical factors with cfDNA-derived CNA signatures, and validated it using internal and independent external cohorts. Conclusion Our findings suggest that post-transplant recurrence commonly originates from advanced subclones that emerge late during tumor evolution. The ZJU Criteria provides an accurate, non-invasive strategy that significantly improves pre-LT risk stratification and clinical decision-making for patients with HCC.

To address the growing challenge of an increasing number of elderly lung cancer patients amidst China's aging population and to fill the gap in quality control standards for surgical treatment in this special population, this study aimed to develop a standardized surgical evaluation system for elderly lung cancer patients tailored to China's national conditions. The system was established through a literature review, integrated the pathophysiological characteristics of elderly patients, and was constructed following review, feedback, and revision by experts from multiple thoracic surgery centers. Employing a 100-point scoring system, it comprises three primary domains: physical infrastructure and geriatric adaptability foundational conditions (10 points); management level and perioperative care models (20 points); and technical proficiency and clinical outcomes (70 points). The system places a strong emphasis on geriatric adaptability, proposing specific, quantifiable indicators for age-friendly facility modifications, control of elderly-specific complications, multidisciplinary collaboration, and standardized perioperative management. It provides a convenient and measurable assessment tool for quality control in the surgical treatment of elderly lung cancer in China, which is expected to promote the standardization and homogenization of diagnosis and treatment.

ObjectiveMigraine is a leading neurological disorder and the fourth most common cause of years lived with disability worldwide, affecting nearly 116 million individuals. Although pharmacological treatments are available, their efficacy is often limited by side effects and variable response rates. Repetitive transcranial magnetic stimulation (rTMS) over the dorsolateral prefrontal cortex (DLPFC) offers a safe, non-invasive alternative for migraine management. However, the neurophysiological mechanisms, particularly how rTMS modulates local cortical excitability and distributed pain-related circuits, remain poorly understood. Elucidating these mechanisms is essential for optimizing treatment protocols and improving clinical outcomes. MethodsThis study employed concurrent transcranial magnetic stimulation and electroencephalography (TMS-EEG) to investigate neuroplastic and neurocircuitry mechanisms of DLPFC-rTMS in migraine. Study 1 compared 30 migraineurs and 28 healthy controls to identify abnormalities in TMS-evoked potentials (TEPs) and significant current density (SCD) within sensory-discriminative regions including the primary somatosensory cortex (S1) and posterior insula (pINS), cognitive-affective regions including the anterior insula (aINS) and midcingulate cortex (MCC), and a descending modulatory region, the periaqueductal gray (PAG). Study 2 used a single-blind, crossover, sham-controlled design in 34 healthy participants. Each participant received both active (10 Hz, 80% RMT, 1 500 pulses) and sham DLPFC-rTMS in counterbalanced order. TMS-EEG and cold pain tolerance were assessed before and after each session. ResultsIn Study 1, migraineurs showed a significantly less negative N120 amplitude compared to healthy controls (P=0.027, Cohen’s d=0.60), indicating local intracortical disinhibition. No group differences were observed for N40, P60, or P180 components. At the source level, migraineurs exhibited significantly higher SCD in the S1, pINS, aINS, and MCC (allQ<0.05), but not in the ventroposterior thalamus (vpTHAL), mediodorsal thalamus (mdTHAL), or PAG. In Study 2, active rTMS significantly reduced SCD from pre- to post-stimulation in the S1, aINS, and MCC (all Q<0.05). Sham stimulation also reduced SCD in the S1 (Q<0.05) but not in the aINS or MCC. Although no significant group-level analgesic effect was observed between active and sham conditions (P=0.107), correlation analyses revealed that greater SCD reductions in the S1 and MCC were significantly associated with higher post-rTMS pain tolerance (R=-0.487 and -0.495, both Q<0.01) and larger improvements in pain tolerance(R=-0.487 and -0.451, both Q<0.05). No such correlations were found following sham stimulation, suggesting that the behavioural relevance of neural changes is specific to active rTMS. ConclusionThis study provides novel evidence that migraineurs exhibit both local neuroplastic abnormalities (reduced N120 amplitude) and hyperactivity in key pain-processing regions (S1, pINS, aINS, MCC). A single session of DLPFC-rTMS reduced hyperactivity in the aINS, MCC, and S1. Notably, greater reductions in the S1 and MCC were associated with improved pain tolerance. These findings identify distinct cortical circuitries, particularly within the cognitive-affective pain network, that may serve as potential biomarkers for optimizing rTMS treatment in migraine and other chronic pain conditions. Future studies should validate these results in patient populations experiencing spontaneous migraine attacks and explore multi-session or accelerated rTMS protocols.

Background: and Purpose Ruptured intracranial aneurysms (RIA) are associated with a mortality rate of up to 40% in the Chinese population, highlighting the critical need for targeted treatment interventions for at-risk individuals. Although the impact of aldehyde dehydrogenase 2 (ALDH2) gene mutations on susceptibility to intracranial aneurysms (IA) is well documented, the potential connection between ALDH2 rs671 single-nucleotide polymorphism (SNP) and RIA remains unexplored. Given the increased prevalence of ALDH2 gene mutations among Chinese Han individuals, it is clinically relevant to investigate the link between ALDH2 rs671 SNP and IA rupture. Methods: A prospective study was conducted on 546 patients diagnosed with IA to investigate the association between ALDH2 rs671 SNP and the risk of IA rupture. Results: The ALDH2 rs671 SNP (ALDH2*2) was significantly more prevalent in patients with unruptured IA (UIA) than in those with RIA (32.56% vs. 18.58%, P=0.004). Multivariate logistic regression analysis revealed that people with the ALDH2 mutation (ALDH2*1/*2 and ALDH2*2/*2 gene type) had a significantly reduced odds ratio (OR=0.49; 95% confidence level [CI] 0.27–0.88; P=0.018) for RIAs. Age-specific subgroup analysis indicated that the ALDH2 mutation provided a stronger protective effect in individuals aged 60 years and above with IA compared to those under 60 years old (OR=0.38 vs. OR=0.52, both P<0.05). Conclusion The incidence of RIA was significantly higher in individuals with a normal ALDH2 gene (ALDH2*1/*1) than in those with an ALDH2 rs671 SNP (ALDH2*1/*2 or ALDH2*2/*2). ALDH2 rs671 SNP may serve as a protective factor against RIA in the Chinese Han population.

BACKGROUND: T-cell lymphoblastic lymphoma/acute lymphoblastic leukemia (T-LBL/ALL) is an aggressive form of hematological malignancy associated with poor prognosis in adult patients. Histone deacetylases (HDACs) are aberrantly expressed in T-LBL/ALL and are considered potential therapeutic targets. Here, we investigated the antitumor effect of a novel HDAC inhibitor, chidamide, on T-LBL/ALL. METHODS: HDAC1, HDAC2 and HDAC3 levels in T-LBL/ALL cell lines and patient samples were compared with those in normal controls. Flow cytometry, transmission electron microscopy, and lactate dehydrogenase release assays were conducted in Jurkat and MOLT-4 cells to assess apoptosis and pyroptosis. A specific forkhead box O1 (FOXO1) inhibitor was used to rescue pyroptosis and upregulated gasdermin E (GSDME) expression caused by chidamide treatment. The role of the FOXO1 transcription factor was evaluated by dual-luciferase reporter and chromatin immunoprecipitation assays. The efficacy of chidamide in vivo was evaluated in a xenograft mouse. RESULTS: The expression of HDAC1, HDAC2 and HDAC3 was significantly upregulated in T-LBL/ALL. Cell viability was obviously inhibited after chidamide treatment. Pyroptosis, characterized by cell swelling, pore formation on the plasma membrane and lactate dehydrogenase leakage, was identified as a new mechanism of chidamide treatment. Chidamide triggered pyroptosis through caspase 3 activation and GSDME transcriptional upregulation. Chromatin immunoprecipitation assays confirmed that chidamide led to the increased transcription of GSDME through a more relaxed chromatin structure at the promoter and the upregulation of FOXO1 expression. Moreover, we identified the therapeutic effect of chidamide in vivo . CONCLUSIONS This study suggested that chidamide exerts an antitumor effect on T-LBL/ALL and promotes a more inflammatory form of cell death via the FOXO1/GSDME axis, which provides a novel choice of targeted therapy for patients with T-LBL/ALL.
Humans ; Pyroptosis/drug effects* ; Forkhead Box Protein O1/genetics* ; Aminopyridines/pharmacology* ; Animals ; Mice ; Benzamides/pharmacology* ; Cell Line, Tumor ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Phosphate-Binding Proteins/metabolism* ; Histone Deacetylase Inhibitors/pharmacology* ; Jurkat Cells ; Histone Deacetylases/metabolism* ; Apoptosis/drug effects* ; Gasdermins