Inflammation Research最新文献

Background: Pyroptosis, a proinflammatory form of programmed cell death, has emerged as a central driver of chronic inflammation, CD4⁺ T cell depletion, and non-AIDS comorbidities in HIV infection. This review synthesizes current evidence on the molecular mechanisms and pathological consequences of pyroptosis in HIV.

Methods: We conducted a comprehensive analysis of the literature, examining the molecular pathways of pyroptosis triggered by abortive HIV infection, the roles of specific inflammasomes (e.g., AIM2, NLRP3, CARD8) and viral proteins, and the subsequent amplification of inflammation through cytokine release and gut barrier dysfunction.

Results: Abortive infection in resting CD4⁺ T cells generates cytosolic viral DNA, activating inflammasomes (primarily AIM2/IFI16) and executing pyroptosis via GSDMD. This process initiates a vicious cycle of immune activation, mucosal damage, microbial translocation, and systemic inflammation, leading to CD4⁺ T cell loss, reservoir persistence, and end-organ damage. Therapeutic targeting of key nodes (e.g., caspase-1, NLRP3, GSDMD) shows promise in preclinical models.

Conclusion: Pyroptosis is a critical pathological engine in HIV, linking viral infection to chronic immunodeficiency and comorbidities. Adjunctive therapies targeting this pathway may reduce inflammation, preserve immune function, and support strategies toward a functional cure.

Background: Chronic neuroinflammation is increasingly recognized not as a secondary effect but as a primary driver of neurodegenerative disease progression. In conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington's disease (HD), and Lewy body dementia (LBD), dysregulated glial activity, marked by sustained microglial and astrocytic activation, initiates a cascade of cytokine release, oxidative stress, and impaired neuronal support. This review synthesizes recent advances in understanding these shared inflammatory processes, emphasizing how glia-centric pathology shapes disease-specific trajectories and therapeutic responses.

Findings: Within this framework, we evaluate the therapeutic potential of semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) with emerging neuroprotective properties. Preclinical studies suggest that semaglutide can suppress pro-inflammatory signaling, mitigate oxidative injury, and enhance key anti-inflammatory and neuroprotective pathways that restore trophic support and cellular resilience. We also examine real-world evidence and emerging human clinical trial data, which recently demonstrated that semaglutide rapidly modulates AD pathology by significantly reducing cerebrospinal fluid (CSF) levels of p-tau, t-tau, and neurogranin, and promoting a less inflammatory CD8⁺T-cell signature. In addition to reduction in neuroinflammation marker, YKL-40. While subsequent large-scale Phase 3 trials in early AD did not meet primary cognitive endpoints (CDR-SB) despite favorable biomarker modulation.

Conclusion: Positioning semaglutide as a therapeutic option targeting neuroinflammation-mediated neuropathology, this review underscores its potential for repurposing as a disease-modifying therapy across diverse neurodegenerative disorders and highlights the urgent need for targeted trials in MS, ALS, FTD, HD, and LBD-conditions that remain without effective immunomodulatory treatments despite clear inflammatory origins. However, while direct CSF measurements confirm limited but measurable BBB penetration, the clinical translation of its effects remains a key challenge.

Background: Acute respiratory distress syndrome (ARDS) and systemic immune-mediated damage are two of the severe COVID-19 outcomes that are primarily caused by cytokine storms triggered by dysregulated immune responses. The limited benefits of current immunosuppressive treatments highlight the need for mechanistic understanding to direct focused interventions.

Objective: The dual functions of cytokines in controlling autophagy during SARS-CoV-2 infection are examined in this review, along with the potential for autophagy modulation to limit hyperinflammation and restore immune homeostasis.

Key findings: Emerging evidence suggests that autophagy critically modulates the balance between pro- and anti-inflammatory cytokines in COVID-19. Through anti-inflammatory feedback mechanisms, cytokines contribute to resolution while promoting inflammation in the early stages. The IRE1α-XBP1 axis is activated by SARS-CoV-2-induced endoplasmic reticulum stress, which increases cytokine production and modifies autophagic flux. Concurrently, extracellular vesicles containing cytokines, damage-associated molecular patterns, and viral components are released as secretory autophagy reroutes cytoplasmic cargo toward multivesicular bodies and amphisomes, increasing paracrine immune activation. Suppressed degradative autophagy and increased secretory autophagy-mediated inflammatory signaling are the hallmarks of this pathological state.

Conclusions: In severe COVID-19, targeted autophagy restoration is a promising therapeutic approach to restore immune responses, reduce excessive inflammation, and encourage the resolution of cytokine storms. Restoring immune homeostasis through more targeted immunointerventions may be made possible by modifying autophagy pathways.

Introduction: Potential increased cancer risk associated with janus kinase inhibitors (JAKi) compared with anti-tumor necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA) remains a concern. Published cohort studies have reported conflicting results, and the discrepancies between randomized trials and real-world data remain unclear. We conducted this systematic review and meta-analysis to assess this association.

Material/methods: We systematically searched PubMed, Embase and Cochrane Library for cohort studies up to January 31, 2025, comparing JAKi with TNFi and reporting cancer outcomes in RA patients. The primary outcome was overall cancer risk, and secondary outcomes included site-specific cancers. Pooled hazard ratios (HR) with 95% confidence intervals (CI) were calculated using a random-effects meta-analysis. Subgroup and sensitivity analyses were conducted to explore potential sources of heterogeneity. The certainty of evidence (CoE) were assessed using the GRADE framework.

Results: We included 5 cohort studies with 137,640 RA patients. Compared to TNFi, JAKi did not increase the risk of overall cancers (pooled HR: 1.06, 95% CI: 0.81-1.37; CoE: very low). Regarding secondary outcomes, JAKi was not linked to most cancers but increased the risk of non-melanoma skin cancer (NMSC) (HR: 1.21, 95% CI: 1.03-1.41; CoE: very low). The finding was consistent across multiple subgroup and sensitivity analyses.

Conclusion: This meta-analysis found no increase in overall cancer risk with JAKi compared to TNFi, but identified an increased risk of NMSC, suggesting the need for regular dermatologic surveillance.

Background: Intervertebral disc degeneration (IVDD), a primary cause of chronic low back pain, involves extracellular matrix (ECM) degradation and nucleus pulposus cell apoptosis. While traditionally linked to mechanical stress, inflammation, oxidative stress, and metabolic dysfunction, emerging evidence positions circadian clock disruption as the central hub integrating these factors. Under physiological conditions, the core clock genes BMAL1/CLOCK regulate ECM homeostasis.

Results: In IVDD, however, this rhythm is disrupted: abnormal mechanical stress inhibits BMAL1 via the RhoA/ROCK pathway; inflammation (e.g., IL-1β) suppresses BMAL1 transcription through NF-κB, creating a vicious cycle; aging-related oxidative stress and ferroptosis are exacerbated by BMAL1 epigenetic silencing; and metabolic disorders promote NLRP3 inflammasome activation via mTORC1-mediated autophagy suppression and miR-155-dependent BMAL1 mRNA decay. Consequently, circadian dysregulation accelerates ECM breakdown and mitochondrial apoptosis. This synthesis establishes a novel 'circadian-centric' model of IVDD, unifying multifactorial pathogenesis under the framework of rhythm disruption. It reveals precise pathways such as RhoA/BMAL1/ECM, bridging key mechanistic gaps. Therapeutically, this model advocates a paradigm shift from symptomatic management to circadian rhythm reconstruction. Potential strategies include restoring BMAL1 rhythmicity to reverse ECM catabolism, targeting the circadian-inflammatory axis (e.g., melatonin, IL-1β antagonists) to concurrently mitigate inflammation and oxidative damage, and employing chrono-therapeutic interventions such as timed mechanical loading or nighttime drug administration.

Conclusion: This review provides a foundational rationale for developing chrono-precise diagnostics and treatments, aiming to redefine IVDD management toward endogenous rhythm restoration.

Objective: Ischemic heart disease (IHD) is one of the leading causes of death globally, and the process of myocardial repair after myocardial infarction (MI) is complex and crucial. Recent studies have underscored the pivotal role of cardiac-resident macrophages in the salvage of infarcted myocardium. This literature review summarizes recent findings on the central regulatory function of the activating transcription factor 3 (ATF3) in regulating macrophage behavior and macrophage-cardiomyocyte crosstalk during post-MI myocardial repair.

Methods: A comprehensive review of recent experimental and translational studies was conducted, focusing on ATF3 mediated regulation of macrophage activation, polarization, functional plasticity, and intercellular communication in the context of ischemic heart injury and repair.

Results: ATF3, a stress-responsive transcription factor, is a key mediator in oxidative stress and ischemic injury responses across diverse cellular milieus.The complexity of ATF3's role in regulating macrophage involvement in myocardial repair stems from multiple factors: the cell types expressing ATF3 can affect its function; the stage of disease progression may alter ATF3's role; and ATF3's activity is regulated not only at the expression level but also by post-translational modifications such as ubiquitination and SUMOylation. These factors collectively contribute to the intricate regulation of ATF3. Moreover, the origin of macrophages also dictates their multidimensional role in myocardial repair.

Conclusions: The ATF3-macrophage axis represents a critical regulatory network in post-MI myocardial repair. Elucidating its context dependent and cell specific mechanisms may provide novel therapeutic insights for modulating post infarction inflammation and improving cardiac repair outcomes.

The recent proposal by Xie et al. that KIAA1429 silencing ameliorates osteosarcoma progression primarily by promoting ferroptosis via the Nrf2/NQO1 axis offers a valuable yet potentially oversimplified mechanistic model. While this finding underscores the significant link between the m6A writer KIAA1429 and redox homeostasis, our critical appraisal identifies several conceptual oversights that challenge the directness and exclusivity of this pathway. The core vulnerability lies in attributing the complex phenotypic outcome of silencing a global RNA modifier to a single downstream axis, without conclusive genetic rescue evidence to establish Nrf2's indispensable role. Moreover, the pleiotropic nature of KIAA1429, which regulates a vast transcriptome encompassing other key ferroptosis regulators (e.g., GPX4, SLC7A11), is largely overlooked. The translational potential of targeting KIAA1429 is further questioned by the lack of assessment regarding on-target toxicities in normal cells, such as osteoblasts and mesenchymal stem cells, and the foreseeable resistance mechanisms via functional redundancy within the m6A machinery. This commentary urges a more nuanced interpretation of the data and highlights the formidable pharmacological challenges that must be overcome before KIAA1429 can be considered a viable therapeutic target.

Background: Asthma is the most common respiratory disorder with airway inflammation and alterations. Included among comorbidities with asthma are psychiatric conditions; however, it is unclear how these disorders engaging with each other.

Findings: In type-2-high asthma, allergens cause airway type-2 immune responses with respiratory symptoms. When the patients experience high blood levels of pro-inflammatory cytokines, they can promote reactive glial cell-induced neuroinflammation and hyperactivation of the thalamus, insula, and cingulate cortex, responsible for interoceptive states, as well as those of the hippocampus/amygdala, contributing to emotions, via the blood-cerebrospinal fluid barrier structure and cerebrospinal fluid system. The prefrontal cortex controls these brain regions to maintain cognitive responses in harmony with interoception and emotion, while over time, dysregulation of the prefrontal cortex is induced. This likely prompts cognitive-perceptual bias-related cognitive distortion or catastrophic thinking of respiratory symptoms and asthma-dependent emotions, which, rather than airway sensory hyperinnervation, may mediate uncontrollable respiratory sensory perception, leading to a spiral along with asthma symptoms.

Conclusion: Collectively, it is hypothesized that type-2 immune responses initiate airway abnormalities, while neuroinflammation and neuronal hyperactivation can induce brain neural network disruption with psychiatric episodes, presumably enhancing the progression of asthma. The notion predicts novel therapeutics for type-2-high asthma comorbid with psychiatric disorders.

The recent study by Yu et al. (2025) elucidates a critical mechanism linking mechanical stress to mitochondrial dysfunction in osteoarthritis (OA), demonstrating that Piezo1 activation is associated with impaired PINK1/Parkin-mediated mitophagy, leading to chondrocyte injury and cartilage degradation. While this work significantly advances our understanding of OA pathogenesis by integrating biomechanical and bioenergetic perspectives, key aspects require further exploration. Specifically, the downstream signaling mechanisms mediated by calcium influx, the potential role of reactive oxygen species (ROS) and inflammasome activation, and alternative therapeutic strategies beyond Piezo1 inhibition warrant deeper investigation. This commentary highlights these avenues for future research and emphasizes the importance of targeting mitochondrial quality control as a promising approach for OA therapy.