HLA-mismatched allogeneic adoptive immune therapy in patients with severely immunosuppressed AIDS: a multicenter, open-label, controlled, phase 2a study.

Recurrent opportunistic infections (OIs) in patients with severely immunosuppressed AIDS remain an unresolved medical challenge despite advancements in antiretroviral therapy (ART). To address this gap, we developed an HLA-mismatched allogeneic adoptive immune therapy (AAIT) specifically targeting this patient population. The safety and efficacy of this novel therapeutic approach were preliminarily confirmed in our phase 1 trial. Subsequently, a multicenter, open-label, controlled, phase 2a trial was conducted to evaluate the efficacy of AAIT in combination with ART compared with the conventional ART-only regimen. No difference in the incidence of adverse events (AEs) was observed between the two groups at the 96-week follow-up. AAIT treatment improved CD4+ T cell recovery at weeks 72 (P = 0.048) and 96 (P = 0.024) compared to the Control Group. Additionally, stratified analysis of patients in the AAIT Group showed that donor/recipient sex mismatch was significantly associated with the likelihood of patients achieving an immunological response (OR = 8.667; 95% CI, 2.010-37.377; P = 0.004). These findings suggest that AAIT serves as a promising adjunct therapy for improving the outcomes of patients with severely immunosuppressed AIDS. Further studies are needed to elucidate the immunological mechanisms underlying AAIT and identify the subpopulations that respond optimally to this therapeutic approach. This trial is registered at www.clinicaltrials.gov (NCT04098770).Trial registration: ClinicalTrials.gov identifier: NCT04098770.Trial registration: ClinicalTrials.gov identifier: NCT02651376.

Mitochondria-engine with self-regulation to restore degenerated intervertebral disc cells via bioenergetic robust hydrogel design.

Previous studies have confirmed that intervertebral disc degeneration (IDD) is closely associated with inflammation-induced reactive oxygen species (ROS) and resultant cell mitochondrial membrane potential (MMP) decline. Clearance of ROS in an inflammatory environment is essential for breaking the vicious cycle of MMP decline. Additionally, re-energizing the mitochondria damaged in the inflammatory milieu to restore their function, is equally important. Herein, we proposed an interesting concept of mitochondrion-engine equipped with coolant, which enables first to "cool-down" the inflammatory environment, next to restore the MMP, finally to allow cells to regain normal energy metabolism through materials design. As such, we developed a multi-functional composite composed of a reactive oxygen species (ROS)-responsive sodium alginate/gelatin hydrogel infused into a rigid 3D-printed thermoplastic polyurethane (TPU) scaffold. The TPU scaffold was coated with conductive polypyrrole (PPy) to electrophoretically deposit l-arginine, which could upregulate the Mammalian target of rapamycin (mTOR) pathway, thus increasing MMP and energy metabolism to stimulate extracellular matrix synthesis for IVD repair. While the ROS-responsive hydrogel acting as the "mito-engine coolant" could scavenge the excessive ROS to create a favorable environment for IVD cells recovery. Demonstrated by in vitro and in vivo evaluations, the mito-engine system markedly promoted the proliferation and collagen synthesis of nucleus pulposus cells while enhancing the mitochondrial respiration and MMP under oxidative stress. Radiological and histological assessments in vivo revealed the efficacy of this system in IVD repair. This unique bioinspired design integrated biomaterial science with mitochondrial biology, presents a promising paradigm for IDD treatment.

A comparison of anterior reconstruction of spinal defect using nano-hydroxyapatite/polyamide 66 cage and autologous iliac bone for thoracolumbar tuberculosis: a stepwise propensity score matching analysis.

Purpose: Previous studies have confirmed the advantages and disadvantages of autogenous iliac bone and nano-hydroxyapatite/polyamide 66 (n-HA/PA66) cage. However, there is no conclusive comparison between the efficacy of the two implant materials in spinal tuberculosis bone graft fusion. The aim of this study was to analyze the mid-to long-term clinical and radiologic outcomes between n-HA/PA66 cage and autogenous iliac bone for anterior reconstruction application of spinal defect for thoracolumbar tuberculosis. Methods: We retrospectively reviewed all patients who underwent anterior debridement and strut graft with n-HA/PA66 cage or iliac bone combined with anterior instrumentations between June 2009 and June 2014. One-to-one nearest-neighbor propensity score matching (PSM) was used to match patients who underwent n-HA/PA66 cage to those who underwent iliac bone. Clinical outcomes were assessed using the Japanese Orthopaedic Association (JOA) and visual analogue score (VAS). Radiographic evaluations included cage subsidence and segmental angle. Results: At the end of the PSM analysis, 16 patients from n-HA/PA66 cage group were matched to 16 patients in Iliac bone group. The C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) values in the n-HA/PA66 group decreased significantly from 33.19 ± 10.89 and 46.63 ± 15.65 preoperatively, to 6.56 ± 2.48 and 9.31 ± 3.34 at the final follow-up, respectively (p < 0.001). There were no significant differences in the CRP and ESR values between the two groups at the final follow-up. The VAS and JOA scores in the iliac bone and n-HA/PA66 group were significantly improved at the 3-month follow-up postoperatively (both p < 0.001). Then, improvements of VAS and JOA scores continue long at final follow-up. However, there were no significant differences in the VAS and JOA scores at any time point between the two groups (p > 0.05). Although the segmental angle (SA) significantly increased after surgery in both groups, there was no significant difference at any time point after surgery (p > 0.05). There were no significant differences in the cage subsidence and fusion time between the two groups. Conclusion: Overall, our data suggest that the n-HA/PA66 cage outcomes are comparable to those in the autogenous iliac bone, with a similar high fusion rate as autogenous iliac bone.

Activating Angiogenesis and Immunoregulation to Propel Bone Regeneration via Deferoxamine-Laden Mg-Mediated Tantalum Oxide Nanoplatform.

Vascularization and inflammation management are essential for successful bone regeneration during the healing process of large bone defects assisted by artificial implants/fillers. Therefore, this study is devoted to the optimization of the osteogenic microenvironment for accelerated bone healing through rapid neovascularization and appropriate inflammation inhibition that were achieved by applying a tantalum oxide (TaO)-based nanoplatform carrying functional substances at the bone defect. Specifically, TaO mesoporous nanospheres were first constructed and then modified by functionalized metal ions (Mg2+) with the following deferoxamine (DFO) loading to obtain the final product simplified as DFO-Mg-TaO. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) revealed that the product was homogeneously dispersed hollow nanospheres with large specific surface areas and mesoporous shells suitable for loading Mg2+ and DFO. The biological assessments indicated that DFO-Mg-TaO could enhance the adhesion, proliferation, and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). The DFO released from DFO-Mg-TaO promoted angiogenetic activity by upregulating the expressions of hypoxia-inducible factor-1 (HIF-1α) and vascular endothelial growth factor (VEGF). Notably, DFO-Mg-TaO also displayed anti-inflammatory activity by reducing the expressions of pro-inflammatory factors, benefiting from the release of bioactive Mg2+. In vivo experiments demonstrated that DFO-Mg-TaO integrated with vascular regenerative, anti-inflammatory, and osteogenic activities significantly accelerated the reconstruction of bone defects. Our findings suggest that the optimized DFO-Mg-TaO nanospheres are promising as multifunctional fillers to speed up the bone healing process.

Surgical Treatment Outcomes of Anterior-Only Correction and Reconstruction for Severe Cervical Kyphotic Deformity with Neurofibromatosis-1: A Retrospective Study with a 5-Year Follow-Up.

OBJECTIVES: Currently, anterior-only (AO), posterior-only, and combined anterior-posterior spinal fusions are common strategies for treating cervical kyphosis in patients with neurofibromatosis-1 NF-1. Nevertheless, the choice of surgical strategy remains a topic of controversy. The aim of our study is to evaluate the safety and effectiveness of anterior decompression and spinal reconstruction for the treatment of cervical kyphosis in patients with NF-1. METHODS: Twelve patients with NF-1-associated cervical kyphotic deformity were reviewed retrospectively between January 2010 and April 2020. All patients underwent AO correction and reconstruction. The X-ray was followed up in all these patients to assess the preoperative and postoperative local kyphosis angle (LKA), the global kyphosis angle (GKA), the sagittal vertical axis, and the T1 slope. The visual analog scale score, Japanese Orthopedic Association (JOA) score, and neck disability index (NDI) score were used to evaluate the improvement inclinical symptoms. The results of the difference in improvement from preoperatively to the final follow-up assessment were assessed using a paired t-test or Mann-Whitney U-test. RESULTS: The LKA and GKA decreased from the preoperative average of 64.42 (range, 38-86) and 35.50 (range, 10-81) to an average of 16.83 (range, -2 to 46) and 4.25 (range, -22 to 39) postoperatively, respectively. The average correction rates of the LKA and GKA were 76.11% and 111.97%, respectively. All patients had achieved satisfactory relief of neurological symptoms (p < 0.01). JOA scores were improved from 10.42 (range, 8-16) preoperatively to 15.25 (range, 11-18) at final follow-up (p < 0.01). NDI scores were decreased from an average of 23.25 (range, 16-34) preoperatively to an average of 7.08 (range, 3-15) at the final follow-up (p < 0.01). CONCLUSION: Anterior-only correction and reconstruction is a safe and effective method for correcting cervical kyphosis in NF-1 patients. In fixed cervical kyphosis cases, preoperative skull traction should also be considered.

Machine learning for predicting liver and/or lung metastasis in colorectal cancer: A retrospective study based on the SEER database.

OBJECTIVE: This study aims to establish a machine learning (ML) model for predicting the risk of liver and/or lung metastasis in colorectal cancer (CRC). METHODS: Using the National Institutes of Health (NIH)'s Surveillance, Epidemiology, and End Results (SEER) database, a total of 51265 patients with pathological diagnosis of colorectal cancer from 2010 to 2015 were extracted for model development. On this basis, We have established 7 machine learning algorithm models. Evaluate the model based on accuracy, and AUC of receiver operating characteristics (ROC) and explain the relationship between clinical pathological features and target variables based on the best model. We validated the model among 196 colorectal cancer patients in Beijing Electric Power Hospital of Capital Medical University of China to evaluate its performance and universality. Finally, we have developed a network-based calculator using the best model to predict the risk of liver and/or lung metastasis in colorectal cancer patients. RESULTS: 51265 patients were enrolled in the study, of which 7864 (15.3 %) had distant liver and/or lung metastasis. RF had the best predictive ability, In the internal test set, with an accuracy of 0.895, AUC of 0.956, and AUPR of 0.896. In addition, the RF model was evaluated in the external validation set with an accuracy of 0.913, AUC of 0.912, and AUPR of 0.611. CONCLUSION: In this study, we constructed an RF algorithm mode to predict the risk of colorectal liver and/or lung metastasis, to assist doctors in making clinical decisions.

Increased LACTB2 Expression Regulates Oxidative Phosphorylation and mTORC1 Signaling of Colorectal Cancer.

This study aimed to investigate the mechanisms of LACTB2 in colorectal cancer (CRC). Microarrays and sequencing data of CRC were acquired from UCSC Xena, GTEx, Gene Expression Omnibus, and TCGA. Pooled analysis of the mRNA expression of LACTB2 in CRC was performed using Stata software. The protein expression of LACTB2 in CRC tissues was evaluated by immunohistochemistry. The relationship between immune cell infiltration and LACTB2 expression was investigated using CIBERSORT. The potential signaling pathways and biological mechanisms of LACTB2 were explored using GSEA, KEGG, and GO. Subsequently, further screening of small molecular compounds with potential therapeutic effects on CRC was conducted through the HERB database, followed by molecular docking studies of these compounds with the LACTB2 protein. The integration and analysis of expression data obtained from 2294 CRC samples and 1286 noncancerous colorectal samples showed that LACTB2 was highly expressed in CRC. Immunohistochemistry performed on in-house tissue samples confirmed that LACTB2 protein expression was upregulated in CRC. CIBERSORT revealed lower B cell infiltration levels in the high LACTB2 expression group than in the low expression group. GO, KEGG, and GSEA analyses showed that LACTB2 expression and genes positively correlating with it were mainly related to DNA synthesis and repair, mitochondrial translational elongation and translational termination, phosphorylation, and mTORC1 signaling. Finally, molecular docking simulations confirmed the ability of quercitin to target and bind to LACTB2. This is the first study to demonstrate that LACTB2 is upregulated in CRC. LACTB2 promotes colorectal tumorigenesis and tumor progression.

Interface-induced dual-pinning mechanism enhances low-frequency electromagnetic wave loss.

Improving the absorption of electromagnetic waves at low-frequency bands (2-8 GHz) is crucial for the increasing electromagnetic (EM) pollution brought about by the innovation of the fifth generation (5G) communication technology. However, the poor impedance matching and intrinsic attenuation of material in low-frequency bands hinders the development of low-frequency electromagnetic wave absorbing (EMWA) materials. Here we propose an interface-induced dual-pinning mechanism and establish a magnetoelectric bias interface by constructing bilayer core-shell structures of NiFe2O4 (NFO)@BiFeO3 (BFO)@polypyrrole (PPy). Such heterogeneous interface could induce distinct magnetic pinning of the magnetic moment in the ferromagnetic NFO and dielectric pinning of the dipole rotation in PPy. The establishment of the dual-pinning effect resulted in optimized impedance and enhanced attenuation at low-frequency bands, leading to better EMWA performance. The minimum reflection loss (RLmin) at thickness of 4.43 mm reaches -65.30 dB (the optimal absorption efficiency of 99.99997%), and the effective absorption bandwidth (EAB) can almost cover C-band (4.72 ~ 7.04 GHz) with low filling of 15.0 wt.%. This work proposes a mechanism to optimize low-frequency impedance matching with electromagnetic wave (EMW) loss and pave an avenue for the research of high-performance low-frequency absorbers.

The ERK-cPLA2-ACSL4 axis mediating M2 macrophages ferroptosis impedes mucosal healing in ulcerative colitis.

Ulcerative colitis (UC) is a chronic gastrointestinal disease that can be managed with 5-aminosalicylic acid (5-ASA), the standard treatment for UC. However, the effectiveness of 5-ASA is not always optimal. Our study revealed that despite 5-ASA treatment, cells continued to experience excessive ferroptosis, which may hinder mucosal healing in UC and limit the success of this treatment approach in achieving disease remission. We found that combining 5-ASA with the ferroptosis inhibitor Fer-1 led to a significant inhibition of ferroptosis in macrophages present in the colon tissue, along with an increase in the proportion of M2 macrophages, suggesting that targeting ferroptosis in M2 macrophages could be a potential therapeutic strategy for alleviating UC. Our study also demonstrated that M2 macrophages are more susceptible to ferroptosis compared to M1 macrophages, and this susceptibility is associated with the activated arachidonic acid (AA) metabolism pathway mediated by ERK-cPLA2-ACSL4. Additionally, we found that the expression of cPLA2 gene pla2g4a was increased in the colon of UC patients compared to healthy controls. Furthermore, targeted metabolomics analysis revealed that the combination treatment group, as opposed to the 5-ASA treatment group, exhibited the ability to modulate AA metabolism. Overall, our findings emphasize the importance of addressing macrophage ferroptosis in order to enhance macrophage anti-inflammation, improve mucosal healing, and achieve better therapeutic outcomes for patients with UC.

Preoperative geriatric nutritional risk index is useful factor for predicting postoperative delirium among elderly patients with degenerative lumbar diseases.

PURPOSE: It is the first study to evaluate the predictive value of the geriatric nutritional risk index (GNRI) on postoperative delirium (POD) after transforaminal lumber interbody fusion (TLIF) in elderly patients with degenerative lumbar diseases. METHODS: A retrospective study was conducted to assess the outcomes of TLIF surgery in elderly patients with lumbar degenerative disease between the years 2016 and 2022. Delirium was diagnosed by reviewing postoperative medical records during hospitalization, utilizing the Confusion Assessment Method. The geriatric nutritional risk index was calculated using the baseline serum albumin level and body weight. Multivariate logistic regression analysis was employed to identify the association between preoperative GNRI and postoperative delirium (POD). Additionally, a receiver operating characteristic curve was utilized to determine the optimal GNRI cutoff for predicting POD. RESULTS: POD was observed in 50 of the 324 patients. The GNRI was visibly reduced in the delirium group. The mean GNRI was 93.0 ± 9.1 in non-delirium group and 101.2 ± 8.2 in delirium group. On multivariate logistic regression, Risk of POD increases significantly with low GNRI and was an independent factor in predicting POD following TLIF (OR 0.714; 95% CI 0.540-0.944; p = 0.018). On receiver operating characteristic curve, the area under curve (AUC) for GNRI was 0.738 (95% CI 0.660-0.817). The cutoff value for GNRI according to the Youden index was 96.370 (sensitivity: 66.0%, specificity: 70.4%). CONCLUSION: Our study indicated that lower GNRI correlated significantly with POD after TLIF. Performing GNRI evaluation prior to TLIF may be an effective approach of predicting the risk for POD among elderly patients with degenerative lumbar diseases.

Orbital septum attachment site on the levator aponeurosis sling for mild congenital blepharoptosis.

PURPOSE: This study aimed to investigate the value of the orbital septum attachment site on the levator aponeurosis (OSASLA) sling in correcting mild congenital blepharoptosis. METHODS: A total of 60 patients (92 eyes) with mild congenital blepharoptosis (levator function ≥ 8 mm) were treated in our hospital from January to October 2021, and relevant data of these patients were collected. All patients underwent OSASLA sling for ptosis correction. The distances from the superior tarsal border to the OSASLA were measured. The primary outcome was the number of postoperative changes in the marginal reflex distance 1 (MRD1). Pearson's correlation coefficient between the distance from the superior tarsal border to the OSASLA and the height of the upper eyelid elevated was analyzed. RESULTS: Fifty-eight patients (89 eyes) successfully underwent OSASLA sling surgery. The preoperative MRD1 was 1.4-3.6 mm (mean 2.1 ± 0.5 mm), and the postoperative MRD1 was 3.4-5.0 mm (mean 3.7 ± 0.6 mm). The distance from the superior tarsal border to the OSASLA sling was significantly and positively correlated with the height of the upper eyelid elevation (r = 0.7328, P < 0.0001). The eyelid margin positions of the patients did not regress substantially during 6-18 months of follow-up. CONCLUSIONS: Compared with the shortening of levator palpebrae superioris (LPS) and pleating of LPS, the OSASLA sling is a less invasive, more effective, and easy-operating surgery for mild congenital blepharoptosis.

Ferroptosis: a promising candidate for exosome-mediated regulation in different diseases.

Ferroptosis is a newly discovered form of cell death that is featured in a wide range of diseases. Exosome therapy is a promising therapeutic option that has attracted much attention due to its low immunogenicity, low toxicity, and ability to penetrate biological barriers. In addition, emerging evidence indicates that exosomes possess the ability to modulate the progression of diverse diseases by regulating ferroptosis in damaged cells. Hence, the mechanism by which cell-derived and noncellular-derived exosomes target ferroptosis in different diseases through the system Xc-/GSH/GPX4 axis, NAD(P)H/FSP1/CoQ10 axis, iron metabolism pathway and lipid metabolism pathway associated with ferroptosis, as well as its applications in liver disease, neurological diseases, lung injury, heart injury, cancer and other diseases, are summarized here. Additionally, the role of exosome-regulated ferroptosis as an emerging repair mechanism for damaged tissues and cells is also discussed, and this is expected to be a promising treatment direction for various diseases in the future. Video Abstract.

The Comparison of Posterior Intervertebral Release Combined with Posterior Column Osteotomy and Posterior Column Osteotomy Alone for the Treatment of Moderate-to-Severe Rigid Scoliosis: A Prospective Controlled Study.

OBJECTIVES: There is no consensus on the treatment of moderate-to-severe rigid scoliosis. Anterior release and three-column osteotomy are excessively traumatic, whereas posterior column osteotomy (PCO) alone results in poor outcomes. An emerging surgical technique, posterior intervertebral release (PR), can release the rigid spine from the posterior approach. This study was performed to compare the multi-segment apical convex PR combined with PCO and PCO alone in patients with moderate-to-severe rigid scoliosis. METHODS: From June 2021 to June 2022, this prospective study of moderate-to-severe (Cobb: 70-90°) rigid scoliosis (flexibility of main curve <25%) involved two groups defined by surgical procedure: the PR group, the patients undergoing PR combined with PCO; and the PCO group, the patients undergoing PCO alone. Follow-up was at least 12 months. Radiographic results mainly included main curve Cobb, correction of per PR/PCO segment, apical vertebra rotation (AVR) and apical vertebra translation (AVT). Demographics, surgical data, complications were also recorded. Student's independent samples t test and Pearson's chi-square test were used to compare the differences between groups. RESULTS: Forty patients with an average age of 16.65 years were included (PR group, n = 20; PCO group, n = 20). The main curves averaged 77.56° ± 5.86° versus 78.02° ± 5.72° preoperatively and 20.07° ± 6.73° versus 33.58° ± 5.76° (p < 0.001) at the last follow-up in the PR and PCO groups, respectively. The mean correction rates were 74.30% and 56.84%, respectively (p < 0.001). The average coronal curve correction was 13.49° per release segment, which was significantly higher than the PCO correction of 6.20° (p < 0.001). The correction of apical vertebra rotation and translation in the main thoracic curve was significantly better in the PR group than in the PCO group (p < 0.05). Several minor complications in the two groups improved after conservative treatment. CONCLUSION: The multi-segment apical convex PR combined with PCO offers more advantages than PCO alone in the treatment of patients with moderate-to-severe rigid scoliosis. Owing to its excellent corrective effect and few complications, this is a high benefit-risk ratio surgical strategy for rigid scoliosis.

The Association between High Preoperative MRI-based Vertebral Bone Quality (VBQ) Score and Titanium Mesh Cage Subsidence after Anterior Cervical Corpectomy and Fusion.

OBJECTIVE: Recently, the MRI-based vertebral bone quality (VBQ) score has been shown to correlate with Hounsfeld units (HU) value, dual-energy X-ray absorptiometry (DEXA) T-score and predict osteoporotic fractures. Preoperative cervical HU value is an independent correlative factor for early titanium mesh cage (TMC) subsidence after anterior cervical corpectomy and fusion (ACCF). However, to date the direct association between cervical VBQ score and TMC subsidence has not been studied. This study aims to investigate the predictive effect of cervical VBQ score derived from sagittal non-contrast-enhanced T1-weighted MRI on the early TMC subsidence after ACCF. METHODS: Patients who underwent one-level ACCF from January 2016 to January 2020 were included. We retrospectively collected baseline data on age, sex, body mass index (BMI), disease type, level of surgery and radiology parameters. The cervical VBQ score was measured using preoperative non-contrast-enhanced T1-weighted MRI. Univariate and multivariate logistic regression analysis were performed to screen the independent risk factors of TMC subsidence. The receiver operating characteristic (ROC) curve and area under curve (AUC) were performed to assess the predictive ability of TMC subsidence based on the cervical VBQ score. Spearman correlation analysis was used to determine the correlations between the cervical VBQ score and TMC subsidence. RESULTS: A total of 134 patients who underwent one-level ACCF were included in this study, and 46 (34.33%) patients had TMC subsidence. Univariable analyses demonstrated that the age, TMC placement depth and VBQ score were associated with subsidence. The cervical VBQ score in the subsidence group was significantly higher than that in the no subsidence group (3.75 ± 0.45 vs. 3.20 ± 0.42, p < 0.001). The multivariate logistic regression analysis proved that the higher VBQ score (odds ratio[OR] = 13.563, 95% confidence interval [CI] 4.968 - 37.031, p < 0.001) was the only variable that significantly predicted subsidence. Using a VBQ score cutoff value of 3.445, the cervical VBQ score yielded a sensitivity of 69.6% and a specificity of 85.2% with an AUC of 0.810 to differentiate patients with subsidence and with no subsidence. CONCLUSION: Preoperative higher cervical VBQ score is an independent risk factor for TMC subsidence after ACCF. The cervical VBQ score may be a valuable tool for assisting in distinguishing the presence of TMC subsidence.

Lupeol alleviates autoimmune myocarditis by suppressing macrophage pyroptosis and polarization via PPARα/LACC1/NF-κB signaling pathway.

BACKGROUND: Autoimmune myocarditis, with increasing incidence and limited therapeutic strategies, is in urgent need to explore its underlying mechanisms and effective drugs. Pyroptosis is a programmed cell death that may contribute to the pathogenesis of myocarditis. Nonetheless, no direct evidence validated the role of pyroptosis in autoimmune myocarditis. Lupeol (Lup), a pentacyclic triterpene, possesses various biological activities such as antidiabetic properties. However, the effects of Lup on autoimmune myocarditis and pyroptosis remain unelucidated. PURPOSE: This study aimed to reveal the role of pyroptosis in autoimmune myocarditis and explore the protective effects of Lup, and its engaged mechanisms. METHODS: The experimental autoimmune myocarditis (EAM) mouse model was established by immunization with a fragment of cardiac myosin in Balb/c mice. Lup and MCC950 were administered after EAM induction. The protective effects were assessed by inflammation score, cardiac injury, chronic fibrosis, and cardiac function. Mechanistically, the effects of Lup on the M1 polarization and pyroptosis of macrophages were evaluated. Transcriptome sequencing and molecular docking were subsequently employed, and the underlying mechanisms of Lup were further explored in vitro with small interfering RNA and adenovirus. RESULTS: Administration of Lup and MCC950 alleviated EAM progression. Western blotting and immunofluorescence staining identified macrophages as the primary cells undergoing pyroptosis. Lup inhibited the expression of pyroptosis-associated proteins in macrophages during EAM in a dose-dependent manner. Furthermore, Lup suppressed pyroptosis in both bone marrow-derived macrophages (BMDMs) and THP-1-derived macrophages in vitro. In addition, Lup inhibited the M1 polarization of macrophages both in vivo and in vitro. Mechanistically, the protective effects of Lup were demonstrated via the suppression of the nuclear factor-κΒ (NF-κB) signaling pathway. Transcriptome sequencing and molecular docking revealed the potential involvement of peroxisome proliferator-associated receptor α (PPARα). Subsequently, we demonstrated that Lup activated PPARα to reduce the expression level of LACC1, thereby inhibiting the NF-κB pathway and pyroptosis. CONCLUSION: Our findings indicated the crucial role of macrophage pyroptosis in the pathogenesis of EAM. Lup ameliorated EAM by inhibiting the M1 polarization and pyroptosis of macrophages through the PPARα/LACC1/NF-κB signaling pathway. Thus, our results provided a novel therapeutic target and agent for myocarditis.