Depression is linked to microglial activation, but the precise triggers and downstream pathways remain elusive. Through single-cell RNA sequencing of human blood samples, we find upregulation of the CCL5-CCR5 axis in patients with major depressive disorder. Using a chronic social defeat stress mouse model, we show that CCR5 is specifically elevated in activated hippocampal microglia. Microglia-specific deletion of CCR5 alleviates depressive-like behaviors and prevents microglial activation. Mechanistically, CCR5 binding to VHL stabilizes HIF-1α, redirecting microglial metabolism toward aerobic glycolysis. This metabolic shift results in lactate accumulation, which drives histone H4 lysine 12 lactylation (H4K12la). Genome-wide profiling reveals that H4K12la enrichment at complement gene promoters facilitates their transcription, ultimately leading to excessive microglial engulfment of neuronal spines and synaptic loss. Importantly, either inhibiting glycolysis or exogenous lactate supplementation can respectively rescue or mimic the pathological synaptic pruning and depressive-like behaviors. Our findings indicate a CCR5-driven immune-metabolic-transcriptional axis in microglia that underlies synaptic deficits in depressive-like behaviors, offering potential targets for therapeutic intervention.

Insufficient understanding of α-synuclein turnover mechanisms has impeded successful clinical translation for Parkinson's disease (PD). Here, we pinpointed cholesterol 25-hydroxylase (CH25H) as a pivotal regulator of α-synuclein degradation. Through bulk RNA sequencing of substantia nigra tissue from the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, along with reanalysis of published datasets from induced pluripotent stem cell-derived astrocytes of patients with PD, we observed an elevated CH25H expression in PD-associated astrocytes. This finding was validated by combined fluorescence in situ hybridization for Ch25h and immunofluorescence staining for GFAP in mouse substantia nigra sections. Conditional knockout or knockdown of astrocytic Ch25h alleviated PD-like motor deficits and reduced dopaminergic neuronal loss in MPTP and α-synuclein preformed fibril (PFF) mouse models. Using 4D label-free proteomics and molecular docking approaches, we uncovered a shared binding domain on p62 where both CH25H and α-synuclein interact. Proximity ligation assays in cultured astrocytes showed that Ch25h overexpression promoted formation of p62/CH25H complex, whereas it inhibited p62/α-synuclein interaction. Conversely, Ch25h knockdown enhanced p62/α-synuclein complex formation and facilitated α-synuclein degradation. 25-Hydroxycholesterol, the enzymatic by-product of CH25H, did not affect the expression of α-synuclein in astrocytes, suggesting an activity-independent influence of CH25H on α-synuclein clearance. In addition, treatment with a p62 polypeptide (60 to 90 amino acids) effectively facilitated α-synuclein clearance by sequestering free CH25H in both cultured astrocytes and mice in the PFF model. Collectively, our study provides insights into the mechanisms underlying α-synuclein turnover and suggests promising avenues for disease-modifying interventions in synucleinopathies.

Background: Rho GTPase-activating protein 40 (ARHGAP40), downregulated in various tumors, including basal cell carcinoma, has an unclear role in colorectal cancer (CRC). This study aimed to elucidate the function and clinical significance of ARHGAP40 in CRC. Methods: ARHGAP40 expression in CRC tissues was evaluated by immunohistochemistry and analyzed in relation to clinicopathological features and patient survival. Gain-and loss-of-function experiments were performed in CRC cell lines to assess cell proliferation, apoptosis, migration, and invasion. RNA sequencing, co-immunoprecipitation, Ras homolog gene family member A (RhoA) activation assays, and rescue experiments were conducted to explore the underlying mechanism. Results: ARHGAP40 expression was significantly decreased in CRC tissues and cell lines. Low ARHGAP40 expression was associated with poor differentiation (p < 0.001), deeper tumor invasion (p = 0.004), lymph node metastasis (p < 0.001), advanced TNM stage (p < 0.001), and unfavorable prognosis in patients with CRC (p < 0.05). Functional experiments showed that ARHGAP40 overexpression suppressed CRC cell proliferation, migration, and invasion, while promoting apoptosis, whereas ARHGAP40 knockdown exerted opposite effects. Mechanistically, ARHGAP40 interacted with RhoA and negatively regulated its activation. Moreover, restoration of RhoA activity partially reversed the effects of ARHGAP40 overexpression on CRC cell proliferation and apoptosis. Conclusions: ARHGAP40 is downregulated in CRC, and its loss may contribute to tumor progression, possibly through dysregulation of RhoA activity.

BackgroundThe liver-brain axis influences outcomes after acute brain injury, yet the prognostic significance of liver markers across varying injury types remains unclear. We examined the disease-specific prognostic value of the aspartate aminotransferase-to-alanine aminotransferase ratio (AAR) in traumatic brain injury (TBI), intracerebral hemorrhage (ICH), and aneurysmal subarachnoid hemorrhage (aSAH).MethodsThis retrospective cohort study included 1,069 consecutive patients (413 TBI, 490 ICH, 166 aSAH). The primary outcome was unfavorable neurological status at discharge (modified Rankin Scale 3–6). Multivariable logistic regression and formal interaction testing assessed the heterogeneity of AAR’s effect across disease types.ResultsUnfavorable outcomes occurred in 420 patients (39.3%). Higher AAR was associated with poor outcomes in the overall cohort (adjusted OR 1.34, 95% CI: 1.07–1.66). However, significant effect modification by disease type was observed (P for interaction = 0.001). In TBI, elevated AAR was a robust independent predictor (adjusted OR 2.15, 95% CI: 1.46–3.15, p < 0.001), with the magnitude of association escalating with injury severity (Severe TBI: adjusted OR 5.38). Conversely, AAR showed no significant prognostic value in ICH (p = 0.746) or aSAH (p = 0.810). A significant dose–response relationship between AAR and unfavorable outcome was observed across the overall cohort (P for trend < 0.001), and the prognostic effect of AAR in TBI escalated markedly with injury severity.ConclusionThe prognostic value of AAR is highly heterogeneous. It serves as a powerful predictor in TBI—likely reflecting systemic metabolic stress—but lacks utility in hemorrhagic stroke. These findings suggest distinct pathophysiological mechanisms driving liver-brain interactions across neurosurgical conditions, cautioning against a “one-size-fits-all” biomarker approach.

Maladaptive learned fear responses to stress underlie several debilitating neuropsychiatric disorders. Here, we identify a brain-to-spleen neural pathway that mediates learned fear through coordinated neuroimmune interactions. Using a chronic acquired olfactory stress (CAOS) model, we demonstrate that sustained enhancement of the piriform cortex (Pir) excitability contributes to the transformation of stress-associated olfactory inputs into learned fear-avoidance behavior. Through comprehensive neural tracing approaches, we mapped a functional tetrasynaptic circuit (Pir→ventral hippocampus CA1 subregion [vCA1]→CeM→DVC→spleen) regulating T helper 17 (Th17) cell-dependent fear responses. Single-nucleus RNA sequencing revealed that olfactomedin 3-expressing glutamatergic neurons in the Pir integrate olfactory stress inputs to activate this pathway. Importantly, targeted disruption of this circuit through either conditional knockdown of Olfm3 within Pir→vCA1 projecting glutamatergic neurons or chemogenetic inhibition of these projections eliminated CAOS-induced splenic Th17 cell expansion and fear avoidance. These findings provide fundamental insights into how learned fear becomes maladaptive by identifying a complete neural circuit linking olfactory perception to peripheral immunity.

AIMS:Traumatic brain injury-induced coagulopathy (TBI-IC) frequently occurs after TBI, exacerbating the severity of TBI and affecting patient prognosis. Benzbromarone (BBR) is commonly used to treat hyperuricemia; however, its protective effects against TBI-IC remain unknown. Therefore, we explored whether BBR could improve TBI. MATERIALS AND METHODS:C57BL/6 wild-type mice were subjected to fluid percussion injury to mimic TBI, and BBR was administered intraperitoneally 30 min after TBI. Magnetic resonance imaging (MRI) and Evans blue dye extravasation were used to assess the prognosis, tail bleeding time, ELISA, and coagulation tests assess coagulation function. We further explored the potential mechanism by which BBR alleviates hypercoagulation after TBI using flow cytometry. KEY FINDINGS:The intraperitoneally injected BBR group showed improved survival and neurological severity scores compared to the TBI group. Subsequently, we found that hypercoagulability developed 3 h after TBI and that the administration of BBR improved this hypercoagulability. BBR also reduced the degree of platelet phosphatidylserine (PS) exposure after TBI, platelet activation, and Ca2+ overload, in addition to inhibition of scramblase activity in procoagulant platelets. SIGNIFICANCE:Our findings indicate that BBR reduces PS externalization by inhibiting TMEM16F expression, thereby improving blood hypercoagulability after TBI.

Anlotinib, an anti-angiogenic agent, has demonstrated significant anti-tumor effects in non-small cell lung cancer (NSCLC). However, whether anlotinib exerts its anti-tumor activity in NSCLC through ferroptosis, and its underlying mechanisms, remain unclear. This study revealed that anlotinib effectively inhibited the proliferation of NSCLC cells in a time- and dose-dependent manner. Treatment with anlotinib resulted in increased levels of ferroptosis targets (lipid reactive oxygen species and malondialdehyde) and p53 protein expression, while decreasing glutathione levels and the protein expression of solute carrier family 7 member 11 (xCT) and glutathione peroxidase 4 (GPX4). Notably, the ferroptosis inhibitor, Ferrostatin-1 (Fer-1), or the p53 inhibitor, Pifithrin-α (PFT-α), reversed the observed effects on ferroptosis induction in NSCLC cells. Consistently, our in vivo studies showed accelerated tumor growth rates for the anlotinib/Fer-1 group and the anlotinib/PFT-α group compared with administration of anlotinib alone. However, anlotinib-induced ferroptosis was suppressed in p53-deficient cells. Collectively, these findings confirm that anlotinib exerts potent anti-tumor effects both in vitro and in vivo by inducing ferroptosis by modulating the p53/xCT/GPX4 pathway specifically within NSCLC cells.

Background:Due to the undesirable cumulative toxicity of multiple drugs, de-escalated neoadjuvant chemotherapy strategies are needed for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Pyrotinib, a small-molecule irreversible pan-HER receptor tyrosine kinase inhibitor, shows promising efficacy in the neoadjuvant setting. We aimed to determine the efficacy, safety and predictive biomarkers of the de-escalated neoadjuvant nab-paclitaxel combined with pyrotinib and trastuzumab in intrinsic HER2-enriched breast cancer. Methods:In this multicenter phase 2 study (NCT05659056), patients who were histologically diagnosed with HER2-positive breast cancer (clinical stage ⅡA-ⅢC) were deemed suitable to participate in this study. Participants received pyrotinib (400 mg once), trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg maintenance dose), and nab-paclitaxel (260 mg/m2) on day 1 of each 3-week cycle for six cycles. The primary endpoint was the rate of total pathological complete response (tpCR) among BluePrint HER2-enriched breast cancers, which was defined as complete disappearance of invasive tumor in breast specimen and all sampled axillary lymph nodes (ypT0/is, ypN0). This study has been completed. Findings:Between 3 December 2022 and 6 June 2024, 74 participants were finally enrolled in the study. Of all enrolled participants, 66 had baseline BluePrint and MammaPrint results. Among the 43 participants with BluePrint HER2-enriched breast cancer, 23 achieved tpCR (53%, 95% CI 38%-69%), and 28 achieved breast pathological complete response (bpCR) (65%, 95% CI 49%-79%). Among the 23 participants with non-HER2-enriched subtypes, 7 achieved tpCR (30%, 95% CI 13%-53%), while 10 achieved bpCR (43%, 95% CI 23%-66%). Of 66 participants with MammaPrint risk score index, the tpCR rate in MammaPrint ultra-high group (24/39) was significantly higher than that in high group (6/27, P = 0.0024). With the median follow-up of 19.9 months (IQR, 15.5-25.4), no cases of recurrence, metastasis, or mortality events were observed. Grade 3-4 treatment-related adverse events occurred in 17 (23%) participants. The most common grade 3-4 adverse event was diarrhea (10/74). No treatment-related deaths occurred. Of all enrolled participants, no treatment discontinuations occurred due to disease progression during the neoadjuvant therapy period. Interpretation:De-escalated neoadjuvant cytotoxic chemotherapy regimen is promising for BluePrint HER2-enriched breast cancer. Our results provide critical references for the efficacy and biomarkers of de-escalated neoadjuvant therapy in HER2-positive breast cancer. Funding:National Natural Science Foundation of China and Natural Science Foundation of Jiangsu Province.

Cross-talk between the nervous and immune systems is involved in neurological diseases. However, their potential interplay in depression has yet to be elucidated. Here, using single-cell RNA and neutrophil SMART RNA sequencing, we showed that CCR5+ neutrophils were significantly increased in patients with depression and preferentially migrated to the hippocampus in a mouse model of depression. Infiltrated neutrophils engulf neuronal spines and subsequently promote depressive symptoms in male mice. Furthermore, by genetic or pharmacologic disruption, we identified a chemotactic effect of the astrocyte-derived chemokine CCL5 on mediating the infiltration of CCR5+ neutrophils and behavioral disorders in male depressed mice. Our findings therefore highlight the critical role of neutrophils in depression pathogenesis and astrocytes in mediating the dysregulation of innate immune responses and suggest that inhibition of CCL5/CCR5-mediated neutrophil infiltration represents a potential therapeutic strategy for noninfectious brain diseases such as depression.

This comprehensive review sought to investigate the correlation between PLR and LMR with overall longevity (OS), recurrence-free interval (DFS), and malignancy-related survival (CSS) among individuals diagnosed with colorectal carcinoma. A comprehensive review of relevant studies was carried out using prominent digital repositories to locate research articles that provided hazard estimates (HRs) for PLR and LMR in individuals diagnosed with colorectal cancer. Potential publication bias was examined through graphical funnel plot assessments, while additional subgroup analyses were conducted based on patient demographics and consideration of C-index. Nineteen studies were included for PLR and OS analysis, showing that high PLR was associated with increased mortality risk (HR = 1.23, 95

Cerebral vasospasm (CVS) critically exacerbates secondary brain injury following traumatic brain injury (TBI). Understanding the underlying mechanisms is essential for developing targeted interventions. Methods: We developed a comprehensive murine multimodal imaging platform to evaluate CVS cerebral perfusion, and blood-brain barrier (BBB) integrity, integrating in vivo multiphoton microscopy, magnetic resonance angiography, carotid Doppler ultrasound, and laser speckle contrast imaging with molecular assays and functional assessments. Additionally, we comprehensively analyze single-cell RNA (TBI vs Sham) and bulk-RNA data (NETs-treated vs Control), delineating NETs-driven endothelial injury signatures. Finally, we explored the roles of PAD4-/-, TLR4 inhibition and TREM1 blockade in blocking NETs-induced endothelial injury and CVS, validating key therapeutic targets. Results: Our findings reveal that neutrophil extracellular traps (NETs) stimulate endothelial cells, promoting intracellular accumulation of TREM1, which forms a stable complex with NF-κB. This complex synergistically amplifies TLR4-mediated inflammatory responses, constituting a novel mechanism by which NETs aggravate endothelial injury and vasospasm after TBI. Preclinical interventions aimed at inhibiting NET formation or blocking TREM1 signaling significantly reduced neuroinflammation, cerebral edema, and CVS. Conclusions: These findings identify TREM1 as a promising therapeutic target and illuminate a NET-driven crosstalk between vascular dysfunction and inflammatory cascades in the context of TBI, offering novel translational insights for mitigating secondary brain injury.

Serine Hydroxymethyltransferase 1 (SHMT1) plays a pivotal role in one‐carbon metabolism, facilitating the production of SAM. In this study, dysregulation of one‐carbon metabolism is reported in both Parkinson's disease (PD) patients and animal models, characterized by significantly downregulated expression of SHMT1. Astrocyte‐specific conditional knockout of Shmt1 decreased SAM level, exacerbated motor dysfunction, and dopaminergic neuronal loss in a PD mouse model. While SAM is conventionally generated through the one‐carbon cycle, the data indicate that, despite significant alterations in SHMT1, SAM remains unaffected while labeled 13 C‐Serine. Intriguingly, isotopic labeling experiments revealed a significant association between SHMT1 and the production of PDME, an intermediate metabolite of the phosphatidylethanolamine methylation pathway. Consequently, PEMT is discovered as interacting with SHMT1. It is demonstrated that disruption of the interaction between SHMT1 and PEMT leads to SAM depletion, causing H3K4me1 hypomethylation, which in turn reduces the expression of Slc1a2 and Glul. As a result, decoupling of SHMT1 and PEMT in astrocytes ultimately exacerbates neuroexcitotoxicity and dopaminergic neuron loss in PD. Thus, the study elucidates the novel metabolic connection between SHMT1 and PEMT that links the astrocytic one‐carbon cycle and membrane phospholipid metabolism in PD.

Although a fraction of functional peptides concealed within long non-coding RNAs (lncRNAs) is identified, it remains unclear whether lncRNA-encoded peptides are involved in the malignancy of cervical cancer (CC). Here, a 92-amino acid peptide is discovered, which is named TUBORF, encoded by lncRNA TUBA3FP and highly expressed in CC tissues. TUBORF inhibits ferroptosis to promote the malignant proliferation of CC cells. Mechanistically, human papillomavirus (HPV) oncogenes E6 and E7 upregulate TUBORF through CREB-binding protein (CBP)/E1A-binding protein p300 (p300)-mediated histone H3 lysine 27 acetylation (H3K27ac) of lncTUBA3FP enhancer. Furthermore, E6 and E7 elevate and recruit acetyltransferase establishment of sister chromatid cohesion N-acetyltransferase 1 (ESCO1) to bind to and acetylate TUBORF, which facilitates the degradation of immunity-related GTPase Q (IRGQ) via a ubiquitin-proteasome pathway, resulting in the inhibition of ferroptosis and promotion of the malignant proliferation of CC cells. Importantly, silencing ESCO1 or TURORF amplifies anticancer effects by paclitaxel both in CC cells and in vivo. These novel findings reveal oncopeptide TUBORF and its acetyltransferase ESCO1 as important regulators of ferroptosis and tumorigenesis during cervical cancer pathogenesis and establish the scientific basis for targeting these molecules for treating CC.

Severe Acute Pancreatitis (SAP) is a critical gastrointestinal inflammatory disease. Mesenchymal stem cells (MSCs), multipotent cells exhibiting diverse biological properties including directional migration, paracrine signaling, immunosuppression, and anti-inflammatory effects. Adipose tissue-derived mesenchymal stem cells (ADSCs) are particularly valuable in regenerative medicine and tissue engineering. Previous studies have demonstrated that ADSCs can mitigate pancreatic damage during acute pancreatitis (AP). However, given the complexity of SAP pathophysiology, which involves a dysregulated systemic inflammatory response and multiorgan failure, the therapeutic differences and underlying mechanisms of ADSCs derived from distinct harvesting sites. The SAP rat model was created by retrograde injection of a 4

Neutrophils are the first responders among peripheral immune cells to infiltrate the central nervous system following a traumatic brain injury (TBI), triggering neuroinflammation that can exacerbate secondary tissue damage. The precise molecular controls that dictate the inflammatory behavior of neutrophils post-TBI, however, remain largely elusive. Our comprehensive analysis of the molecular landscape surrounding the trauma in TBI mice has revealed a significant alteration in the abundance of β2 integrin (ITGB2), predominantly expressed by neutrophils and closely associated with immune responses. Using the fluid percussion injury (FPI) mouse model, we investigated the therapeutic efficacy of Rovelizumab, an agent that blocks ITGB2. The treatment has demonstrated significant improvements in neurologic function in TBI mice, attenuating blood–brain barrier permeability, mitigating oxidative stress and inflammatory mediator release, and enhancing cerebral perfusion. Moreover, ITGB2 blockade has effectively limited the adherence, migration, and infiltration of neutrophils, and has impeded the formation of neutrophil extracellular traps (NETs) upon their activation. Finally, it was demonstrated that ITGB2 mediates these effects mainly through its interaction with intercellular adhesion molecule-1 (ICAM 1) of endotheliocyte. These findings collectively illuminate ITGB2 as a crucial molecular switch that governs the adverse effects of neutrophils post-TBI and could be targeted to improve clinical outcome in patients.

BACKGROUND:Traumatic brain injury (TBI) causes significant neuronal death, but the underlying mechanisms remain poorly understood. The role of interleukin-23 (IL-23) signaling in post-traumatic neuronal injury requires investigation. METHODS:We examined IL-23 levels in clinical samples from TBI patients and healthy controls. Using a mouse TBI model, we investigated the effects of IL-23 neutralization and explored the cellular mechanisms through analysis of IL-23 receptor expression, JAK2/STAT3 pathway activation, and macrophage infiltration. RESULTS:We found elevated IL-23 levels in both serum and brain tissues of TBI patients. TBI induced neuronal IL-23 receptor expression and activated the JAK2/STAT3 pathway. Infiltrating macrophages were identified as the main IL-23 source, recruited by neuron-derived C-C motif chemokine ligand 2 (CCL2). IL-23 neutralization or CCL2 blockade reduced neuronal ferroptosis and improved neurological outcomes in the mouse model. CONCLUSIONS:Our findings reveal a novel CCL2-macrophage-IL-23 axis in TBI pathogenesis, where IL-23 promotes neuronal ferroptosis through direct receptor-mediated effects. Targeting this pathway represents a potential therapeutic strategy for TBI treatment.

Parkinson’s disease (PD) is a leading neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons, contributing to considerable disability worldwide. Current treatments offer only symptomatic relief, highlighting the need for novel therapeutic strategies targeting disease progression. Neuroinflammation plays a pivotal role in PD pathogenesis, with the NLRP3 inflammasome emerging as a key contributor. The virtual screening of a natural product library comprising 5,088 compounds was applied to identify five potential NLRP3 inhibitors through molecular docking scores. Then surface plasmon resonance assays were used to detect their binding affinities to the NLRP3 protein. Functional studies in macrophages and glial cells were used to demonstrate the effect of Psoralen on NLRP3 phosphorylation and inflammasome activation. Psoralen treatment improved PD-like symptoms and reduced dopaminergic neuronal death by targeting glial NLRP3 inflammasome activation in the MPTP/p mouse model. By performing 4D label-free quantitative phosphorylation proteomics and site mutation assays, we identified that Psoralen prevents NLRP3 phosphorylation at Serine 658 by binding to its NACHT and LRR domains. These findings position Psoralen as a promising NLRP3 inflammasome inhibitor, offering a potential therapeutic avenue for PD and other NLRP3 inflammasome-related diseases. Additionally, this research highlights the innovative approach of targeting specific phosphorylation sites on the NLRP3 protein to reduce neuroinflammation.

Background: Diabetic nephropathy (DN) is the most common and serious complication of diabetes mellitus. Shionone (SH), an important triterpenoid compound in the root extract of Aster, might exert a protective effect in DN mice and high glucose cultivated glomerular podocytes. The current study aimed to unravel the underlying mechanism by which SH mitigates DN. We postulate that SH stimulates the expression of sestrin-2 (SESN2), a pivotal stress-inducible protein in the anti-inflammasome machinery.Methods: We utilized high-fat diet combined with streptozotocin (55 mg/kg intraperitoneal) for DN mice model, and high glucose (30 mM, 48 hours) cultured glomerular podocytes for DN cell model to evaluate the effect of SH. We also preformed experimentation on SESN2 deficiency models (SESN2 knockout mice and SESN2 siRNA in cells) to further prove our hypothesis.Results: The results demonstrated that SH effectively suppressed glomerular fibrosis, induced adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, and inhibited NLR family pyrin domain containing 3 (NLRP3) activation. Furthermore, our findings revealed that SH exerted its anti-inflammatory effect through Sesn2-dependent nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation and subsequent activation of its downstream target heme oxygenase-1 (HO-1).Conclusion: In summary, our findings suggest that SH serves as a promising therapeutic agent for the treatment of DN-related glomerular fibrosis. SH enhances the expression of SESN2, attenuates α-smooth muscle actin accumulation, and suppresses NLRP3-related inflammation through the Nrf2/HO-1 signaling pathway.

Primary mucinous cystadenocarcinoma (MCA) of the breast is an invasive breast carcinoma characterized by cystic structures lined by tall columnar cells with abundant intracytoplasmic mucin, resembling pancreatobiliary or ovarian mucinous cystadenocarcinoma. Fewer than 50 cases have been reported worldwide so far. In this series, we describe the clinical, morphologic, immunohistochemical, and molecular features of 5 cases of breast MCA. The median age of the patients was 54 years (range: 53 to 64 years) and invasive size was 2 mm to 30 mm (our study reported the smallest invasive size to date in case 5). DCIS was present in 4 of 5 cases. Despite the prevailing view that breast MCA may be indolent, our cases exhibit robust growth, characterized by a relatively high Ki67 index, brisk mitosis, and 1 case of micrometastasis of axillary lymph node micrometastasis. Moreover, we conducted large panel sequencing on 4 cases, and emphasize their molecular essence; that is, breast MCA exhibits a high frequency of TP53 mutations and PI3K/AKT pathway alterations. A review of the literature on previous and current genomic profiles indicates that MCAs are similar to triple-negative breast cancer (TNBC). In our opinion, patients with breast MCA should receive precise clinical treatment similarly to invasive breast carcinoma of no special type, with careful consideration of tumor grade, stage, immunophenotype, and genomic profile, and we believe that PI3K-targeted therapies may play a valuable role in treating this rare tumor.

The spread or transmission of pathologic α-synuclein (α-Syn) is emerging as potentially important driver of Parkinson's disease (PD) pathogenesis. Emerging evidence suggests that astrocytes play an important role in uptake/clearance of extracellular α-Syn. However, underlying mechanisms and molecular entities responsible for uptake/clearance of extracellular α-Syn by astrocytes are not known. Here, it is shown that lipocalin-2 (LCN2) is upregulated in astrocytes of MPTP-treated mice by RNA-Seq analysis and positively correlates with pathologic α-Syn level in α-Syn PFF model. Strikingly, deletion of astrocytic LCN2 significantly prevents the pathologic α-Syn accumulation and neurodegeneration. Moreover, 24p3R as a crucial receptor of α-Syn uptake by astrocytes is identified, as well as an important mediator of α-Syn spread in the brain. 24p3R specifically binds to α-Syn and then mediates α-Syn uptake. LCN2 prevents astrocytic uptake of α-Syn by impeding the binding of 24p3R and α-Syn. The identification of LCN2/24p3R as a key regulator of α-Syn by astrocytes provides a new target for the treatment of PD and related α-synucleinopathies.