BACKGROUND: Myocardial ischemia/reperfusion injury (I/RI) represents a serious clinical complication in patients after acute myocardial infarction. Ubiquitin-activating enzyme 1 (UBA1) catalyzes the initial step of ubiquitination and plays a fundamental role in regulating protein homeostasis and related diseases. This study aims to elucidate the functional contribution of UBA1 to the pathogenesis of myocardial I/RI and to uncover its underlying mechanisms. METHODS: Single-cell RNA sequencing was employed to characterize UBA1 expression in human ischemic heart tissues. Myocardial I/R injury was examined in myocardial-specific UBA1 knockout (UBA1cko) mice, UBA1-overexpressing mice (rAAV9-UBA1), and corresponding controls. Neonatal rat cardiomyocytes underwent hypoxia/reoxygenation in vitro. Cardiac function and infarction were evaluated by echocardiography and pathological staining. Protein?protein interactions were analyzed via immunoprecipitation combined with mass spectrometry. The endoplasmic reticulum?mitochondrial contact sites (ERMCSs) and mitochondrial ultrastructure were evaluated through transmission electron microscopy and confocal imaging. RESULTS: UBA1 expression was significantly downregulated in human and murine ischemic myocardium, especially in cardiomyocytes. UBA1cko mice exhibited aggravated I/RI with greater infarct size, impaired function, apoptosis, elevated intracellular Ca2+ levels, mitochondrial dysfunction, and ER stress, whereas UBA1 overexpression conferred cardioprotective effects. Mechanistically, UBA1 directly bound to and ubiquitinated Pdzd8, a key ERMCS-tethering protein, thereby promoting its degradation, which inhibited ERMCS formation and improved mitochondrial dysfunction and ER stress. Moreover, knockdown of Pdzd8 via rAAV9-siRNA effectively mitigated UBA1 knockout-induced myocardial damage. Additionally, administration of auranofin (AF), a U.S. Food and Drug Administration-approved drug for treating rheumatoid arthritis, markedly alleviated myocardial I/RI via activating UBA1 in vivo and in vitro. ### Competing Interest Statement The authors have declared no competing interest.

AIMS:To determine the role of the ubiquitin-activating enzyme UBA1 in macrophage-mediated renal injury during sepsis-associated acute kidney injury (SA-AKI) and to elucidate the underlying molecular mechanism. METHODS AND RESULTS:Using a cecal ligation and puncture mouse model, we evaluated renal function, inflammation, and survival in myeloid-specific Uba1 knockout mice (Uba1M-KO) and littermate controls. Transcriptomic, proteomic, and ubiquitinome analyses were integrated with mechanistic studies in bone marrow-derived macrophages and renal tubular epithelial cell co-cultures. A pharmacologic UBA1 inhibitor (PYR-41) was tested for therapeutic efficacy. UBA1 expression was markedly increased in renal macrophages during SA-AKI. Uba1M-KO mice demonstrated improved survival, preserved renal function, and attenuated inflammatory responses, as evidenced by reduced cytokine production, reactive oxygen species generation, apoptosis, and macrophage infiltration. Mechanistically, UBA1 promoted ubiquitination and degradation of the nuclear pore protein nucleoporin 35 (NUP35), impairing IκBα nuclear import and activating nuclear factor kappa B (NF-κB) signaling. This led to enhanced macrophage inflammatory activation and subsequent renal tubular injury. Pharmacologic inhibition of UBA1 recapitulated the protective effects of genetic deletion in vivo. INNOVATION AND CONCLUSIONS:This study identifies UBA1-mediated NUP35 ubiquitination as a previously unrecognized checkpoint linking ubiquitin activation to nuclear pore integrity and inflammatory signaling in sepsis. UBA1 drives macrophage-mediated inflammation in SA-AKI by promoting NUP35 degradation and subsequent activation of NF-κB signaling. Targeting UBA1 represents a promising immunomodulatory strategy for the prevention and treatment of SA-AKI. Antioxid. Redox Signal. 44, 859-877.

BACKGROUND:Myeloid cell-associated immune responses play a critical role in the pathogenesis of myocardial ischemia/reperfusion (MI/R) injury. Chemokine receptor CXCR2 is expressed mainly in myeloid cells, including neutrophils and macrophages, and is crucial for regulating immune homeostasis. However, the roles of CXCL5 and its receptor CXCR2 in MI/R injury remain unknown. METHODS:To determine the functional significance of CXCL5-CXCR2 axis in MI/R injury, we employed genetic deletion of CXCL5, myeloid-specific deletion of CXCR2, and pharmacological blockade of CXCR2. Cardiac function was evaluated by echocardiography. Myocardial infarct size, apoptosis, and fibrosis were assessed by histological staining. Inflammatory cell infiltration was examined using flow cytometry and immunohistochemistry. Protein and gene expression of signaling mediators and inflammatory markers were analyzed using microarray, qPCR, and immunoblotting. Moreover, circulating CXCR2+ cells and chemokine levels were measured in blood from patients with ST-segment elevation myocardial infarction (STEMI) and controls using flow cytometry and enzyme-linked immunosorbent assay. RESULTS:CXCL5 and CXCR2 expression and the percentage of CXCR2+ immune cells were increased in the heart after I/R injury. CXCL5 deficiency, myeloid-specific deletion of CXCR2, and CXCR2 inhibition improved cardiac function and reduced cardiomyocyte apoptosis, inflammation, oxidative stress, and fibrosis. These protective effects were associated with decreased infiltration of macrophages and neutrophils. Additionally, circulating CD14+ CD16+ CXCR2+ monocytes, CD15+ CD11b+ CXCR2+ neutrophils, and chemokine levels were significantly higher in STEMI patients than in controls. CONCLUSION:The CXCL5-CXCR2 axis represents a promising therapeutic target for MI/R injury and early post-infarct remodeling.

Myocardial ischemia/reperfusion (I/R) injury frequently occurs in acute coronary artery disease after timely reperfusion to rescue the ischemic heart. AMP-activated protein kinase (AMPK) is a key sensor that regulates metabolic metabolism and mitochondrial function and protects against myocardial I/R injury. Thus, pharmacologically activating AMPK modulation of AMPK has been suggested as a potential approach for attenuating myocardial I/R injury. MK-3903 is a potent and selective activator of AMPK, but its importance and mechanism of action in modulating this disease remain unclear. I/R was modeled in wild-type mice pretreated with MK-3903 (30 mg/kg). In addition, hypoxia/reoxygenation (H/R) was modeled using neonatal rat cardiomyocytes (NRCMs), and these cells were treated with MK-3903 and SR-18292 (a PGC-1α inhibitor). Our results revealed that in I/R model mice, the administration of MK-3903 dramatically alleviated myocardial dysfunction; reduced the infarct size, myocyte apoptosis, oxidative stress and inflammation; along with increased AMPK-PGC-1α signaling, improved imitochondrial biogenesis and the balance of mitochondrial dynamics. Conversely, the treatment of NRCMs with SR-18292 markedly diminished the cardioprotective effects of MK-3903 following H/R in vitro. In conclusion, these data demonstrate that MK-3903 may attenuate myocardial I/R injury and mitochondrial dysfunction possibly by activating AMPK-PGC-1α signaling and highlight its potential as a candidate for further investigation in ischemic heart injury.

BackgroundPathological cardiac hypertrophy frequently leads to heart failure (HF). UBA1, the key E1 ubiquitin-activating enzyme, initiates ubiquitin-proteasome signaling and contributes to various diseases, yet its mechanism in cardiac hypertrophy remains unclear.MethodsCardiac hypertrophy model was induced by either Ang II stimulation or TAC in vitro and in vivo. Mice received rAAV9-UBA1-siRNA or rAAV9-UBA1 for UBA1 knockdown or overexpression, respectively.ResultsWe found UBA1 upregulated in murine and human hypertrophic hearts. Cardiomyocyte-specific UBA1 knockdown protected against TAC-induced hypertrophy, fibrosis, oxidative stress, and dysfunction, with downregulation of ATG5 and autophagy induction, whereas myocardial UBA1 overexpression exacerbated these effects. Mechanistically, UBA1 directly interacted with ATG5 and promoted its ubiquitination for degradation, leading to autophagy inactivation and hypertrophy. Furthermore, ATG5 deletion abrogated the protection of UBA1 knockdown against cardiomyocyte hypertrophy.ConclusionsUBA1 regulates cardiac hypertrophy through suppression of ATG5-mediated autophagy and propose UBA1 as a therapeutic target for hypertrophic cardiomyopathy.

Urological malignancies, primarily including renal cell carcinoma, bladder cancer and prostate cancer, underscore the critical importance of early screening, diagnosis and treatment in inhibiting disease progression and improving patient prognosis. Advancements in molecular biology have established urinary biomarkers as promising noninvasive tools with considerable potential for early tumour detection and screening high-risk populations, potentially overcoming limitations associated with traditional invasive procedures and imaging. This review systematically summarises urinary biomarkers related to renal cell carcinoma, bladder cancer and prostate cancer. It focuses on protein biomarkers (e.g., cytokeratin and nuclear matrix protein 22), epigenetic and transcriptional biomarkers (e.g., microRNAs and long noncoding RNAs), genetic biomarkers (e.g., telomerase reverse transcriptase and fibroblast growth factor receptor 3) and emerging biomarkers (metabolomic markers, circulating tumour DNA and mass spectrometry-based high-throughput proteomics). This review provides an in-depth exploration of the molecular mechanisms, diagnostic performance (sensitivity and specificity), current clinical applications and limitations of various biomarkers, placing a particular emphasis on comparing the differential expression of the same biomarker across different cancer types. By building on this foundation, this review further outlines future development pathways, including multibiomarker combination strategies, AI-assisted analysis and standardised testing protocols, to offer comprehensive references for the early, noninvasive and precise diagnosis of urological tumours.

The heterodimeric complex of S100 calcium binding proteins A8 and A9 (S100A8/A9, also known as Calprotectin) is constitutively expressed in myeloid neutrophils and monocytes and plays a role in the modulation of the inflammatory response and cytoskeleton rearrangement. Recently, S100A8/A9 complex has garnered significant attention as a critical alarmin involved in regulating the pathogenesis of various inflammatory cardiovascular diseases, particularly nonischaemic cardiomyopathy (NICM). Furthermore, S100A8/A9 is reportedly associated with the pathophysiological processes of myocardial ischaemia‒reperfusion injury and has also been recognised as a predictor and a potentialmediator of heart failure caused by acutemyocardial infarction. Recent studies have attempted to provide a comprehensive and detailed overview of the involvement of the S100A8/A9 protein in NICM, covering topics such as hypertrophicmyocardial remodelling, septic and dilated cardiomyopathy,myocarditis, chemotherapeutic cardiotoxicity, senescent cardiac dysfunction and cardiac allograft rejection. Ultimately, we aimed to evaluate the application of S100A8/A9 as promising biomarkers and therapeutic strategies for the prediction, prevention and treatment of NICM.

Recent study demonstrated that chronic exposure to solvents increases the risk of Parkinson’s disease (PD), the second most common neurodegenerative disorder characterized by progressive dopaminergic neurodegeneration in the substantia nigra (SN). n -Hexane, a widely used organic solvent, displays central-peripheral neurotoxicity, which is mainly mediated by its active metabolite, 2,5-hexanedione (HD). However, whether HD exposure contributes to PD remains unclear. In this study, we found that rats exposed to HD displayed progressive dopaminergic neurodegeneration in the nigrostriatal system. Microglial activation was also detected in HD-treated rats, which occurred prior to degeneration of dopaminergic neurons. Moreover, depletion of microglia markedly reduced HD-induced dopaminergic neurotoxicity. Mechanistic study revealed an essential role of microglial integrin α M β 2 -NADPH oxidase (NOX2) axis in HD-elicited neurotoxicity. HD activated NOX2 by inducing membrane translocation of NOX2 cytosolic subunit, p47 phox . Integrin α M β 2 was critical for HD-induced NOX2 activation since inhibition or genetic deletion of α M β 2 attenuated NOX2-generated superoxide and p47 phox membrane translocation in response to HD. Src and Erk, two downstream signals of α M β 2 , were recognized to bridge HD/α M β 2 -mediated NOX2 activation. Finally, pharmacological inhibition of α M β 2 -NOX2 axis attenuated HD-induced microglial activation and dopaminergic neurodegeneration. Our findings revealed that HD exposure damaged nigrostriatal dopaminergic system through α M β 2 -NOX2 axis-mediated microglial activation, providing, for the first time, experimental evidence for n -hexane exposure contributing to the etiology of PD.

The polarization of microglia/macrophages is crucial for maintaining the neuroinflammatory response during cerebral ischemia/reperfusion (I/R) injury. Integrin CD11b is implicated in the processes of neuroinflammation, immune regulation, and nerve injury repair. However, its role in microglia- and macrophage-mediated neuroinflammation during cerebral I/R injury remains poorly understood. Wild-type (WT), CD11b knockout (KO), or neutralizing antibody-treated mice were subjected to a transient cerebral artery I/R injury (tMCAO) model. CD11b expression was detected by qPCR, immunofluorescence, and western blotting. Histopathological features were evaluated by H E and Nissl staining, ROS production was detected by DHE staining, neuronal apoptosis was detected by TUNEL assays, and microglia polarization was evaluated by immunofluorescence staining. We discovered that CD11b was significantly increased in the ischemic penumbra following tMCAO. CD11b KO significantly alleviated tMCAO-induced infarct, neurological deficits, oxidative stress, and neuronal apoptosis in the ischemic penumbra. Moreover, CD11b KO significantly enhanced the anti-inflammatory phenotype transition of microglia/macrophages, leading to accelerated inflammation resolution. Furthermore, pharmacological blockade of CD11b demonstrated a protective effect similar to that of CD11b KO. Meanwhile, CD11b deficiency significantly inhibited the activation of p-p65/p-STAT1 signaling pathway and upregulated p-STAT6 expression. In conclusion, CD11b protects against cerebral I/R injury by modulating microglial and macrophage polarization, thereby reducing subsequent neuroinflammation and neuronal death. Our findings suggest that CD11b intervention could be a potential therapeutic strategy for acute cerebral ischemic stroke.

Ethnopharmacological relevance Pulmonary hypertension (PH) is a serious and progressive disease, posing a significant challenge to patient survival and quality of life. However, current treatments have limited effectiveness. Tianlong Kechuanling (TL) is a traditional Chinese medicine (TCM) compound formulation commonly used in clinical practice for the treatment of pulmonary heart disease, but its underlying mechanism is unknown. Aim of the study This study aimed to validate the mitigating effect of TL on PH and to further investigate its mechanism. Materials and methods A rat model of PH was induced by SU5416 combined with hypoxia (SuHx). The effects of TL on PH were evaluated through right ventricular systolic pressure (RVSP), Right ventricular hypertrophy index (RVHI) and histopathological analysis. The serum levels of HIF-1α, VEGFA in rats were detected by ELISA; VEGFR2, Vimentin and CD31 were detected by immunohistochemistry to explore the mechanism of action of TL. Human pulmonary artery endothelial cells (HPAECs) were induced by hypoxia, and the effects of TL were confirmed by RT-PCR and Western Blotting. Liquid chromatography-mass spectrometry (LC-MS) analysis was used to identify the chemical composition of TL. Results TL ameliorated PH through modulation of the HIF-1α/VEGFA pathway and endothelial-to-mesenchymal transition (End-MT). The study also identified the key chemical components responsible for these effects. Conclusions The study demonstrates that TL can improve PH by inhibiting End-MT, supporting the further development of TL as an effective therapeutic option for PH.

BACKGROUND:Myocardial ischemia/reperfusion (I/R) injury is a leading cause of myocardial dysfunction and is associated with inflammation, apoptosis, and fibrosis. The integrin subunit ITGAM (also known as CD11b) mainly mediates leukocyte infiltration in the inflammatory process. However, the importance of CD11b in the development of myocardial I/R injury is unclear. The goal of this study is to investigate the role of CD11b+ immune cells, particularly neutrophils and macrophages, in mediating myocardial I/R injury and to evaluate the therapeutic potential of CD11b inhibition. METHODS:Wild-type mice were administered an anti-CD11b neutralizing antibody before myocardial I/R surgery. Echocardiography and histological staining were used to evaluate cardiac function and injury, respectively. Inflammatory cells were analyzed by flow cytometry in mice and patients with myocardial infarction who underwent percutaneous coronary intervention. Activated fibroblasts from patients with myocardial infarction were detected by positron emission tomography/computed tomography with a [(18)F]-labeled fibroblast activation protein inhibitor. RESULTS:Our results indicated that CD11b expression and the number of CD45+CD11b+ bone marrow mononuclear cells were dramatically increased in the heart tissues of I/R-treated mice. Moreover, compared with immunoglobulin G treatment, the pharmacological inhibition of CD11b in mice greatly alleviated cardiac dysfunction, infarct size, myocyte apoptosis, CD11b+ neutrophils and macrophage infiltration, cardiac fibrosis and fibroblast activation, accompanied by the inhibition of multiple signaling pathways (Bax, caspase-3, nuclear factor-κB, and transforming growth factor-β/Smad2/3) 3 days after I/R surgery. In addition, the numbers of CD15+CD11b+ neutrophils and CD14+CD11b+ monocytes and the levels of inflammatory cytokines (intercellular adhesion molecule -1, vascular adhesion molecule -1, interleukin-1β, and interleukin-6) as well as the levels of fibroblast activation protein inhibitor in patients with myocardial infarction were also significantly greater than those in normal controls. CONCLUSIONS:Our data demonstrate that CD11b plays an important role in promoting myocardial I/R injury through multiple signaling pathways and that targeting CD11b may represent a promising option for treating heart I/R injury.

12/15-Lipoxygenase (LOX) is a member of the LOX family that catalyzes the step from arachidonic acid to hydroxy-eicosatetraenoic acids (HETEs). Previous studies demonstrated that 12/15-LOX plays a critical role in the development of atherosclerosis, hypertension, heart failure, and other diseases; however, its role in myocardial ischemic injury was contraversal. Here, we investigated the inhibition of 12/15-LOX by baicalein on acute cardiac injury and dissected its molecular mechanism. In a mouse model of acute ischemia/reperfusion (I/R) injury, 12/15-LOX was significantly upregulated in the peri-infarct area surrounding the primary infarction. In cultured cardiac myocytes, baicalein suppressed apoptosis and caspase 3 activity in response to simulated ischemia/reperfusion (I/R). Moreover, administration of 12/15-LOX inhibitor, baicalein, significantly attenuated myocardial infarct size induced by I/R injury. Moreover, baicalein treatment significantly inhibited cardiomyocyte apoptosis, inflammatory responses and oxidative stress in the heart after I/R injury. The mechanisms underlying these effects were associated with the activation of ERK1/2 and AKT pathways and inhibition of activation of p38 MAPK, JNK1/2, and NF-kB/p65 pathways in the I/R-treated hearts and neonatal cardiomyoctes. Our data indicated that 12/15-LOX inhibitor baicalein can prevent myocardial I/R injury by modulation of multiple mechanisms, and suggest that baicalein could represent a novel therapeutic drug for acute myocardial infarction.

Rationale: Infiltration of immune cells into the heart plays a crucial role in the transition from adaptive hypertrophy to heart failure (HF) following chronic pressure overload. However, the key factors in myeloid cells that regulate this process are still not well defined. Here, we studied the functional role of S100A8/A9 in myeloid cells during this transition. Methods: Cardiac hypertrophy and HF models were induced by transverse aortic constriction (TAC) for 1 to 4 weeks. The heterogeneity of CD45+ immune cells and the cellular sources of S100A8/A9 were analyzed using published single-cell RNA sequencing datasets. The effects of S100A8/A9 on TAC-induced hypertrophy and HF were verified in S100A9 knockout (KO) and bone marrow (BM)-chimeric mice and in an in vitro coculture system. Results: S100A8/A9 levels were significantly increased in HF patients and in TAC-induced HF model mice. Moreover, the TAC-induced transition from adaptive hypertrophy to HF was significantly attenuated in S100A9-KO mice and WT mice transplanted with S100A9-KO BM cells. Mechanistically, TAC-stimulated upregulation of S100A8/A9 in neutrophils induced an early inflammatory response and adaptive hypertrophy through activation of the p38 MAPK/JNK/AP-1 pathway, leading to increased production of IL-1β and chemokines (CCL2 and CCL6). These chemokines promoted the infiltration of CCR2+ macrophages to the damaged heart. Therefore, they exhibited upregulation of S100A8/A9, which led to exacerbation of inflammation, cardiac hypertrophy and fibrosis via activation of the NF-κB/NLRP3, AKT/Calcineurin A and TGF-β/Smad2 signaling pathways. Additionally, treating WT mice with the S100A9 inhibitor ABR-238901 prevented TAC-induced cardiac hypertrophy-related dysfunction. Conclusion: The present findings establish an S100A8/A9-related axis between myeloid cells and cardiac cells that drives the pressure overload-induced transition from hypertrophy to HF, suggesting that S100A8/A9 is a promising therapeutic target for this disease.

Lipid peroxidation and ferroptosis are critically for the development of cardiac ischaemia-reperfusion (I/R) injury. The proteasome complex is crucial for regulating inflammation and cardiac I/R injury. Proteasome-activating peptide 1 (PAP1) is an activator of the proteasome β5i subunit, but its role in cardiac I/R injury remains unknown. Our results indicate that the administration of PAP1 highly enhanced the expression and activity of the β5i in cardiac tissues possibly by inhibiting of STAT3. Moreover, compared with vehicle control, administration of PAP1 in wild-type mice greatly reversed the I/R-induced decline in myocardial contractility and increases in myocardial infarction, fibrosis, myocyte apoptosis, ROS production and inflammatory response. RNA sequencing revealed that PAP1 mainly affected the genes that were associated with heart contraction, ferroptosis, apoptosis, ROS production and p53. Furthermore, PAP1 clearly decreased the p53 protein and increased the protein levels of SLC7A11 and GPX4 both in mice and cultured cardiomyocytes. Conversely, these protective actions of PAP1 were significantly eliminated in the mice treated with the β5i inhibitor epoxomicin or in the cardiomyocytes transfected with shRNA-β5i but were enhanced by the inhibition of p53 with pifithrin-α. Mechanistically, PAP1 increased the β5i expression, which then bound to p53 and promoted its degradation, resulting in the upregulation of SLC7A11 and GPX4 proteins and the attenuation of oxidative stress and ferroptosis. In summary, our findings suggest that PAP1 can protect against myocardial I/R injury possibly via the β5i-p53-SLC7A11 axis and represent a novel drug candidate for the treating ischaemic heart injury.

OBJECTIVE:The immunoproteasome is linked to endothelial function and may act as a proangiogenic factor. This study explored its predictive value for coronary collateral circulation (CCC) in ST-elevation myocardial infarction (STEMI) patients. METHODS:We enrolled 252 STEMI patients from April 2021 to April 2024. Plasma levels of LMP2, LMP7, and PSMB10 were measured using ELISA. ROC curves assessed predictive ability for good CCC. Univariate and multivariate logistic regression analyses identified predictors, and restricted cubic spline (RCS) analysis evaluated the dose-response relationship. Subgroup analysis was also conducted. RESULTS:Patients with good CCC had significantly higher plasma levels of immunoproteasome components. Among them, LMP7 showed the best predictive value (AUC = 0.732), with an optimal cut-off of 3.824 ng/mL. Multivariate logistic regression confirmed LMP7 ≥3.824 ng/mL as an independent predictor for good CCC [OR = 7.914 (4.127-15.174)]. RCS analysis showed a J-shaped association: the odds of good CCC increased notably when LMP7 exceeded 3.824 ng/mL. Subgroup analyses supported these findings. CONCLUSION:Higher plasma immunoproteasome levels, especially LMP7 ≥3.824 ng/mL, were independently associated with good CCC in STEMI patients, suggesting its potential role as a biomarker of collateral development.

In the original publication [...].

Macrophages in the liver play an important role in the development of sepsis-associated liver dysfunction (SALD). Ubiquitin-activating enzyme E1 (UBA1) is critically involved in protein degradation and inflammatory diseases. However, whether UBA1 in macrophages participates in the development of SALD remains unknown. Sepsis and acute liver injury mouse models were established by caecal ligation and puncture (CLP) in macrophage-specific UBA1-knockout (UBA1M-KO) and wild-type (UBA1M-WT) mice. We found that UBA1 expression in liver tissue and macrophages gradually increased and peaked at 48 h after CLP-induced sepsis. Compared with UBA1M-WT mice, UBA1M-KO mice presented an improved survival rate; reduced liver dysfunction, macrophage infiltration, ROS levels, lipid accumulation and hepatocyte apoptosis. In vitro coculture of hepatocytes with macrophages confirmed that UBA1M-KO macrophages ameliorated LPS-induced inflammatory response and hepatocyte injury. Mechanistically, UBA1 interacted with BMAL1 and increased its ubiquitination and degradation, leading to the reduction of REV-ERBα transcriptional activity and subsequent production of proinflammatory cytokines, which ultimately exacerbated SALD. Interestingly, selective inhibition of UBA1 by PYR-41 effectively attenuated SALD. In summary, these findings indicate that macrophage overexpressing UBA1 contributes to the pathogenesis of SALD possibly through regulating the BMAL1-REV-ERBα axis and that targeting UBA1 may represent a promising therapeutic option for the treatment of SALD.