This comprehensive review explores the intricate mechanisms of PANoptosis and its implications in cancer. PANoptosis, a convergence of apoptosis, pyroptosis, and necroptosis, plays a crucial role in cell death and immune response regulation. The study delves into the molecular pathways of each cell death mechanism and their crosstalk within PANoptosis, emphasizing the shared components like caspases and the PANoptosome complex. It highlights the significant role of PANoptosis in various cancers, including respiratory, digestive, genitourinary, gliomas, and breast cancers, showing its impact on tumorigenesis and patient survival rates. We further discuss the interwoven relationship between PANoptosis and the tumor microenvironment (TME), illustrating how PANoptosis influences immune cell behavior and tumor progression. It underscores the dynamic interplay between tumors and their microenvironments, focusing on the roles of different immune cells and their interactions with cancer cells. Moreover, the review presents new breakthroughs in cancer therapy, emphasizing the potential of targeting PANoptosis to enhance anti-tumor immunity. It outlines various strategies to manipulate PANoptosis pathways for therapeutic purposes, such as targeting key signaling molecules like caspases, NLRP3, RIPK1, and RIPK3. The potential of novel treatments like immunogenic PANoptosis-initiated therapies and nanoparticle-based strategies is also explored.

Fibrotic hypersensitivity pneumonitis (FHP) remains one of fatal interstitial pulmonary disease. Comprehensively dissecting the cellular heterogeneity of FHP paves the way for developing general gene therapeutic solutions for FHP. Here, utilizing an integrated strategy based on scRNA-seq, scTCR-seq, and bulk RNA-seq analysis of FHP profiles, we identified ten major cell types and 19 unique subtypes. FHP exhibited higher features of EMT and inflammation-promoting than normal control. In distinct subsets of lung macrophages in FHP, FN1^high, PLA2G7^high, and MS4A6A^high macrophages with predominant M2 phenotype exhibited higher activity of inflammatory responses and para-inflammation than other macrophages. KRT17^high basal-like epithelial cells were significantly increased in FHP, and showed higher ability to induce EMT. We identified roles for ACTA2^high, COL1A1^high, and PLA2G2A^high fibroblasts in FHP, which were significantly related to interstitial fibrosis. NK cells and KLRG1⁺ effector CD8⁺ T cells had greater activity in inflammation-promoting. Our results provide a comprehensive portrait of cellular heterogeneity in FHP, and highlight the indispensable role of cell subpopulations in shaping the complexity and heterogeneity of FHP. These subpopulations are potentially key players for FHP pathogenesis.

Constant exposure to allergen triggers destructive type 2 cell-mediated inflammation. The effect of allergen specific immunotherapy (SIT) in maintaining airway epithelial barrier function in asthma remains unknown. In the current study, we showed that SIT maintained airway epithelial homeostasis in mice exposed to dermatophagoides farinae (Der f), which induced increased expression of IL-25, endoplasmic reticulum (ER) stress and airway epithelial apoptosis. Meanwhile, SIT treatment ameliorated airway inflammatory infiltration and hyper-responsiveness in allergic mice. SIT treatment restored the airway epithelial integrity, attenuated Der f -induced airway epithelial ER stress and epithelial apoptosis. We also found that 4-PBA, an inhibitor of ER stress, suppressed airway epithelial ER stress and apoptosis in vitro. The pathological changes were partially induced by IL-25-induced ER stress, epithelial tight junction damage, and cell apoptosis in airways following allergen exposure. Furthermore, IL-25 induced ER stress in airway epithelial cells in vitro. The IL-25-induced airway epithelial apoptosis dependent on PERK activity was inhibited by 4-PBA. Taken together, we demonstrate that SIT is effective in allergic asthma and dependent on its depressive effect on the expression of IL-25, epithelial integrity damage, and epithelial ER stress.

PM2.5 exposure increases asthma exacerbation risk and worsens airway inflammation and mucus secretion, but the underlying mechanisms, especially the epigenetic modification changes, are not fully understood. ATAC-seq was conducted in Beas-2B cells to explore the differential chromatin accessibilities before and after exposure to PM2.5. RNA-seq was applied to screen the differentially expressed genes (DEGs) as well. The integrated analysis of ATAC-seq and RNA-seq was performed. The key up-regulated genes in the ferroptosis signaling pathway were identified by combined analysis with the FerrDb database and then verified. Meanwhile, to access the role of PM2.5-induced ferroptosis in asthma mice, house dust mites (HDM) were employed to conduct an allergic asthma mice model, and the ferroptosis-specific inhibitor (Ferrostatin-1, Fer-1) was used. The H&E staining, PAS staining, airway hyperresponsiveness, and bronchoalveolar lavage fluid (BALF) cell counting were used to investigate the impact of PM2.5-induced ferroptosis in asthma mice. A total of 4,921 regions with differential accessibility were identified, encompassing 4,031 unique genes. Among these, 250 regions exhibited increased accessibility while 4,671 regions displayed reduced accessibility. Through the integrated analysis of ATAC-seq and RNA-seq, ferroptosis was determined as the key enriched pathway based on up-regulated DEGs and increased chromatin accessibilities. Furthermore, the decreased cell viability, accelerated lipid peroxide and morphological changes in mitochondria observed upon PM2.5 exposure were rescued by Fer-1, which are indicative of ferroptosis. By overlapping with ferroptosis-related genes from the FerrDb database, FTH1 and FTL were identified as the prominent up-regulated genes with increased chromatin accessibility in ferroptosis pathway. In addition, ChIP-qPCR analysis indicated that histone modification like H3K4me3 and H3K27ac positively regulated FTH1 and FTL expression. Subsequently, in PM2.5-exposed asthmatic mice, inhibition of ferroptosis effectively attenuated airway inflammation and mucus secretion. These findings shed light on the molecular mechanisms underlying PM2.5-induced asthma exacerbation, with epigenetic modifications playing a pivotal role. Furthermore, it suggests the therapeutic potential of targeting ferroptosis as an intervention strategy.

Giant magnetoresistive (GMR) biosensors consisting of many rectangular stripes are being developed for high sensitivity medical diagnostics of diseases at early stages, but many aspects of the sensing mechanism remain to be clarified. Using e-beam patterned masks on the sensors, we showed that the magnetic nanoparticles with a diameter of 50 nm located between the stripes predominantly determine the sensor signals over those located on the sensor stripes. Based on computational analysis, it was confirmed that the particles in the trench, particularly those near the edges of the stripes, mainly affect the sensor signals due to additional field from the stripe under an applied field. We also demonstrated that the direction of the average magnetic field from the particles that contributes to the signal is indeed the same as that of the applied field, indicating that the particles in the trench are pivotal to produce sensor signal. Importantly, the same detection principle was validated with a duplex protein assay. Also, 8 different types of sensor stripes were fabricated and design parameters were explored. According to the detection principle uncovered, GMR biosensors can be further optimized to improve their sensitivity, which is highly desirable for early diagnosis of diseases.

Ambrosia artemisiifolia (Amb a) contains many allergens. Allergic conjunctivitis caused by Ambrosia artemisiifolia and its related allergen-specific immunotherapy (AIT) are seldom studied at present. poly(DL-lactide-co-glycolide)-polyethylene glycol (PLGA-PEG) is a very good nano-carrier, which has been applied in the medical field. In this context, we studied the immunotherapy effect and potential mechanism of recombinant Amb a 1 (rAmb a 1)-loaded PLGA-PEG nanoparticles. A mouse allergic conjunctivitis model was established with Ambrosia artemisiifolia crude extract, and the nanoparticles were used for AIT through direct observation of conjunctival tissue, degranulation of mast cells in conjunctival tissue, serum-specific antibodies, cytokines and other assessment models. The treatment of nanoparticles enhanced the secretion of T-helper 1 (Th1) cytokine Interferon-gama (IFN-γ) and the production of immunoglobulin G (IgG)2a (IgG2a), inhibited the secretion of T-helper 2 (Th2) cytokine Interleukin (IL)-13 and IL-4 and the level of IgE. Especially, degranulation of mast cells and expression of mast cell protease-1 (MCP-1) in conjunctival tissue was reduced significantly. In this study, we proved that the nanoparticles prepared by rAmb a 1 and PLGA-PEG have an immunotherapy effect on allergic conjunctivitis in mice.