Ulcerative colitis (UC) is a chronic inflammatory intestinal disorder; however, its exact pathophysiological mechanisms remain elusive. Through integrated RNA-seq and proteome analyses, we revealed that ubiquitin-specific protease 43 (USP43) expression is significantly decreased in dextran sulfate sodium (DSS)-induced colitis. USP43 expression was also lower in UC patients than that in healthy controls. Furthermore, USP43 deficiency in mice exacerbated DSS-induced colitis. In lipopolysaccharide (LPS)-treated RAW264.7 cells, USP43 overexpression inhibited, whereas USP43 knockdown promoted the phosphorylation of p65 and the production of proinflammatory cytokines; NF-κB-specific inhibitor JSH-23 reversed the facilitatory effect of USP43 knockdown on inflammatory cytokines. Mechanistically, USP43 interacts with and deubiquitinates TRAF4, thereby inhibiting NF-κB signaling and reducing proinflammatory cytokine levels. Importantly, TRAF4 overexpression partially reversed the increase in LPS-mediated NF-κB activation caused by USP43 knockdown. Collectively, our findings highlight a novel role for USP43 in suppressing intestinal inflammation through the inhibition of TRAF4-mediated NF-κB activation. These results reveal a new mechanism involving the USP43/TRAF4 axis in the regulation of intestinal inflammation.

Aortic aneurysm (AA) and aortic dissection (AD) are life-threatening vascular diseases characterized by progressive wall degeneration and structural failure. However, the cellular mechanisms underlying their progression and rupture remain poorly understood. We performed integrative single-cell RNA sequencing analysis on four human aortic datasets, including thoracic aortic dissection (TAD), thoracic aortic aneurysm (TAA), abdominal aortic aneurysm (AAA), and ruptured AAA. We identified disease-specific patterns of immune infiltration and vascular structural cell loss. Vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) were reduced in AA but increased in AD. In ruptured AAA, structural cells were nearly absent, with immune cells predominating. In TAD, VSMCs and ECs exhibited marked phenotypic plasticity, transdifferentiating into multiple cell subtypes. Notably, we identified macrophage-like VSMCs and ECs in AD mouse models. Cell-cell communication analysis revealed that macrophages communicated with VSMCs and ECs via the CXCL, IL1B, and SPP1 signaling axes. Importantly, REL, a member of the NF-κB transcription factor family, was identified as a convergent node integrating these inflammatory signals. This study delineates disease-specific transdifferentiation trajectories of ECs and VSMCs during AA and AD progression. Inflammatory macrophages regulate this phenotypic switching via CXCL, IL1B, and SPP1 signaling, activating REL-driven transcriptional programs that compromise vascular integrity. These findings uncover fundamental differences in cellular heterogeneity and injury mechanisms between AA and AD, offering potential therapeutic targets for preventing disease progression and rupture.

Background: Acute lung injury (ALI) is characterized by excessive inflammation and oxidative stress, with macrophages playing pivotal roles in disease progression. The differential survival mechanisms of macrophage subsets during ALI remain poorly understood. Methods: We performed integrated analysis of ALI datasets (GSE11434, GSE237260, GSE264032) and isolated CD14 + macrophages from bronchoalveolar lavage fluid of ALI patients. Murine alveolar macrophages (MH-S) were polarized to M1/M2 phenotypes and subjected to ferroptosis induction. HIF-1 A knockdown and lactate supplementation experiments were performed to investigate metabolic regulation. Myeloid-specific HIF-1 A knockout mice were generated and subjected to LPS-induced ALI. Results: Transcriptomic analysis revealed ferroptosis as a key pathway in ALI, with macrophages showing the highest expression of ferroptosis-related genes. ALI-derived macrophages exhibited enhanced ferroptosis-defense gene expression and elevated lactate production. M1 macrophages demonstrated superior ferroptosis resistance compared to M2 macrophages, associated with higher baseline expression of antioxidant genes and enhanced HIF-1 A signaling. Mechanistically, HIF-1 A in M1 macrophages promoted lactate metabolism, which activated ferroptosis-defense genes through histone lactylation. Myeloid-specific HIF-1 A knockout prevented M1 macrophage survival advantage, reduced inflammatory tissue damage, and alleviated ALI severity. Conclusions: HIF-1 A-mediated lactate metabolism confers ferroptosis resistance in M1 macrophages through epigenetic activation of antioxidant defense genes. This metabolic reprogramming represents a novel therapeutic target for modulating macrophage survival and inflammation in ALI.

Ulcerative colitis is a chronic inflammatory bowel disease with a complex pathogenesis. This study aims to identify novel ferroptosis-related biomarkers and investigate the underlying post-transcriptional regulatory mechanisms in ulcerative colitis. Integrated bioinformatics analysis of public transcriptomic datasets identified key ferroptosis-related hub genes. A dextran sulfate sodium-induced murine colitis model and lipopolysaccharide-stimulated colonic epithelial cells were utilized for experimental validation. Molecular techniques, including RNA immunoprecipitation, mRNA stability assays, and western blot, were employed to elucidate the regulatory axis. We identified RNA Binding Motif Single Stranded Interacting Protein 1 (RBMS1) as a significantly upregulated ferroptosis-related hub gene in ulcerative colitis. Its suppression alleviated both inflammatory injury and ferroptosis in colonic epithelial cells in vitro and in a murine colitis model in vivo. Mechanistically, the N6-methyladenosine reader YTH Domain Containing 2 (YTHDC2) was found to bind RBMS1 transcripts and promote their degradation. YTHDC2 was downregulated in colitis, and its overexpression attenuated disease severity and ferroptosis, whereas concurrent RBMS1 overexpression reversed these protective effects. Our findings reveal a crucial YTHDC2-RBMS1 regulatory axis in ulcerative colitis pathogenesis, wherein decreased YTHDC2 enhances RBMS1 mRNA stability, thereby promoting ferroptosis and inflammation. This axis represents a promising therapeutic target for ulcerative colitis intervention.

Bisphenol A (BPA) is an endocrine-disrupting chemical commonly found in consumer products and is known to induce neuroinflammation and oxidative stress via microglial activation. Carnosic acid (CA), a phenolic diterpene from rosemary (Rosmarinus officinalis L.), has potent antioxidant and neuroprotective properties. This study investigated the protective effects of CA against BPA-induced neuroinflammation and oxidative stress in human HMC3 microglial cells. Firstly, BPA induced the expression of NLRP3 inflammasome–related proteins and increased NLRP3 fluorescence intensity. CA reduced the fluorescence intensity of NLRP3 and cleaved caspase-1 induced by BPA. CA also attenuated BPA-induced protein levels in the inflammasome, proinflammatory cytokines, and phosphorylated tau, as well as the transcription factors FoxO1 and p65. CA improved the effects in BPA-induced ROS level and reduced the expression of catalase, glutathione reductase, superoxide dismutase 2 (SOD2), glutathione peroxidase 1, heme oxygenase-1, nuclear factor erythroid 2-related factor 2 (Nrf2), and UDP-glucuronosyltransferase 1A1 (UGT1A1). In addition, CA restored BPA-suppressed expression of UGT1A1 and SOD2 in the striatum of mice. L-Buthionine-sulfoximine (BSO) treatment abolished CA’s ability to counteract BPA-induced oxidative stress and inflammatory responses. These findings indicated that CA was associated with attenuation of BPA-induced NLRP3 inflammasome-related protein expression and downstream neuroinflammatory signaling by reducing oxidative stress in HMC3 cells.

Intracerebral hemorrhage (ICH) induces neuroinflammation and neuronal damage, partially driven by microglial necroptosis and M1 polarization. Recent evidence implicates red blood cell-derived exosomes (RBC-Exos) in inflammatory pathologies, yet their role in ICH remains unexplored. This study investigates how hemorrhagic RBC-Exos (ICH-Exos) regulate microglial dysfunction and neuropathology through complement signaling. RBC-Exos were isolated and validated using flow cytometry (AnnexinV+CD235+), transmission electron microscopy, nanoparticle tracking analysis, and western blot (CD63/TSG101). In vitro, hemin-treated microglia were exposed to Normal-Exos or ICH-Exos. Murine ICH models assessed neuropathology via histology (H&E, Nissl staining), adhesion molecule expression (ICAM-1/VCAM-1), and neurobehavioral tests. Proteomics identified exosomal protein cargo, complemented by C5 monoclonal antibody (mAb) blocking experiments to dissect mechanistic pathways. ICH-Exos exacerbated hemin-induced microglial necroptosis, marked by upregulated phosphorylated RIPK1, RIPK3, and MLKL, and amplified M1 polarization (elevated CD86, iNOS, CCL2; suppressed CD163, ARG1). In ICH mice, ICH-Exos aggravated cerebral hemorrhage, neuronal loss, and neurobehavioral deficits while elevating pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). Proteomics revealed C5 enrichment in ICH-Exos, correlating with elevated C5a levels in serum and brain tissues. C5 mAb neutralized ICH-Exos effects, rescuing microglial viability, restoring M1/M2 equilibrium, and attenuating necroptosis. In vivo, C5 inhibition reduced hemorrhage volume, restored neuronal Nissl bodies, suppressed ICAM-1/VCAM-1, and mitigated MAPK pathway activation (p-ERK1/2, p-p38). In conclusion, ICH-Exos drive neuroinflammation and neuronal injury post-ICH by promoting C5-dependent microglial necroptosis and M1 polarization. Targeting the C5/C5a axis counteracts these effects, suggesting a novel therapeutic strategy to ameliorate ICH-related neuropathology.

The endogenous cannabinoid system, comprising endocannabinoids, cannabinoid receptors, and enzymes responsible for synthesis and degradation of endocannabinoids, is integral to the regulation of skin inflammation. However, the precise contributions of cannabinoid-metabolizing enzymes including fatty acid amide hydrolase and monoacylglycerol lipase (MAGL) remain poorly defined in psoriatic pathogenesis. In this study, we demonstrated the significant MAGL upregulation in psoriatic lesions and established that pharmacological inhibition of MAGL markedly reduced psoriasiform inflammation and pruritus in imiquimod-challenged C57BL/6 mice. Mechanically, inhibition of MAGL decreased the expression of 12-lipoxygenase (ALOX12), subsequently reducing the synthesis of 12-hydroxyeicosatetraenoic acid (12-HETE), which is the principal metabolite of ALOX12. Importantly, these effects were reversed by cannabinoid receptor 2 (CB2R) antagonism or knockout, establishing a signaling axis in which MAGL inhibition activates CB2R to suppress ALOX12. Collectively, our findings identified MAGL as a potentially targetable nexus in psoriasiform inflammation and itch.