Homozygous pathogenic variants in Ig-like domain of LMNA cause severe segmental progeroid syndromes. Unlike typical HGPS, it remains elusive how these pathogenic variants cause segmental progeroid syndromes. We here reported that affected individuals with LMNAR527C/R527C pathogenic variant developed an atypical segmental progeroid syndrome characterized by autoimmune features. Mesenchymal stem cells (MSCs) derived from these affected individuals exhibited significant inflammation and cellular senescence. In mice, LmnaR527C/R527C pathogenic variant triggered chronic interferon signaling, exacerbated aging-related pathologies, and even induced thymic lymphomas following ionizing radiation. In addition, this pathogenic variant increased susceptibility to inflammation induced by a high-fat diet or LCMV infection. R527C pathogenic variant disrupted the interaction between Lamin A and DNA-binding proteins, causing abnormal protein aggregation and hyperactivation of the cGAS-STING. Importantly, blocking DNA sensing pathways suppressed inflammation, rescued senescence in affected individual-derived MSCs, and alleviated premature aging in LmnaR527C/R527C mice. These findings establish a homozygous LMNA pathogenic variant as a key driver of inflammation-driven segmental progeroid syndrome and highlight DNA sensing pathways as promising therapeutic targets.

Mesenchymal stem cells (MSCs) maintain bone homeostasis through osteogenic differentiation. During aging, MSCs undergo a fate shift toward adipogenesis rather than osteogenesis, but the post-transcriptional mechanisms remain unclear. Here, we identify ovarian tumor domain-containing protein 1 (OTUD1) as an RNA-binding protein that controls MSC fate by stabilizing osteogenic transcripts. OTUD1 directly binds and stabilizes BMP2 mRNA, thereby supporting osteogenic differentiation. In vivo, OTUD1 deficiency does not affect early skeletal development but progressively impairs bone homeostasis during aging and exacerbates bone loss in ovariectomy- and glucocorticoid-induced osteoporosis models. Structure-function analyses reveal that N-terminal intrinsically disordered region of OTUD1 mediates RNA binding and osteogenic activity, whereas its deubiquitinase catalytic domain is dispensable. Multi-omics profiling demonstrates that OTUD1 coordinates the stability of transcripts involved in collagen remodeling and extracellular matrix organization, thereby maintaining MSC stemness and activation. Together, these findings define a mechanism linking RNA stability control to MSC lineage commitment and skeletal homeostasis during aging and disease.

Although immune checkpoint blockade (ICB), including in combination with neoadjuvant regimens, has shown encouraging efficacy in lung cancer, a substantial fraction of patients remains resistant, and the underlying mechanisms are not fully understood. Here, we performed single-cell RNA sequencing of lung squamous cell carcinoma (LUSC) samples collected before and after ICB, stratified by therapeutic outcome. In responders, ICB promoted the expansion of B cells and T follicular helper (Tfh) cells, supporting the formation of tertiary lymphoid structure. In contrast, non-responders exhibited persistent type I interferon (IFN-I) signaling driven by CD36+SPP1+ tumor-associated macrophages, which disrupted lymphoid organization. At baseline, dysfunctional T cells were characterized by aberrant nuclear factor of activated T cells (NFAT) signaling. Mechanistically, IFN-I induced the expression of the phosphatase dual-specificity phosphatase 2 (DUSP2) in pre-exhausted T cells, promoting NFAT dephosphorylation and nuclear accumulation. Nuclear NFAT upregulated inhibitory receptors and antagonized Bcl6-dependent transcriptional programs, thereby reinforcing T cell exhaustion and impairing Tfh differentiation. Genetic ablation of Dusp2 restored CD8+ T cell function and Tfh-B cell interaction, enhancing responsiveness to ICB. These findings identify a pathogenic IFN-I-DUSP2-NFAT axis that limits immunotherapy efficacy in LUSC.

Supplementary Table S3 Comparative p-values for PFS rate and DFS rate in high infiltration group and low-infiltration group, stratified using different cellular characteristics in TCGA.

Supplementary Table S2 Clinicopathological characteristics of patients for scRNA-seq data.

Table S1 Primers used for quantitative real-time PCR.

Supplementary Table S6 PTC-specific markers based on spatial transcriptome screening.

Supplementary Fig. S1 Enrichment of CD36+ pro-inflammatory macrophage in cancer correlates with poor outcome of patients with PTC.

Orthodontic treatment corrects various craniofacial malformations primarily through triggering active alveolar bone remodeling, however the potential impacts of this intervention on the systemic immune state have long been insufficiently explored. Here, we show that mechanical force applied during orthodontic treatment can trigger systemic inflammation dominated by adaptive immune responses. This response not only impairs bone repair at distant body sites but also causes temporary liver dysfunction resembling autoimmune conditions characterized by the expansion of CD69⁺ B cells. Mechanistically, IgM produced by these activated B cells acts as a key pathogenic driver of systemic pathology. Inhibiting the activation of local B cells effectively reversed this immunopathology, underscoring the central role of B cell-derived IgM. We also verified that Piezo1⁺ macrophages function as vital mechanosensors, linking orthodontic mechanical stimulation to B cell activation and subsequent IgM release. Multi-organ metabolomic profiling revealed significant amino acid metabolic dysregulation, which further aggravated systemic inflammation. Crucially, supplementation with lysine and alanine alleviated orthodontic treatment-induced inflammation, restored liver function and promoted distal bone repair. Together, these findings uncover an unrecognized systemic immune-metabolic axis during orthodontic therapy and suggest that targeting B cell-IgM responses or metabolic dysregulation may provide therapeutic opportunities to enhance treatment safety and outcomes.

Supplementary Table S4 The relationship between SPP1 expression and clinicpathologic characteristics in patients with PTC.

Targeted protein degradation (TPD) is a valuable strategy for investigating protein functionality in cell biology and drug discovery. Among the various emerging TPD technologies, antibody-guided TPD offers key advantages over other protein degradation methods in terms of compatibility with different proteins of interest (POIs) and cell types. However, increasing the efficiency of cellular antibody internalisation and protein degradation remains challenges. Inspired by viral infection, which often efficiently activates protein degradation pathways in host cells, we developed a strategy called virus infection-mimicking targeted protein degradation (ViTPD) as a universal platform for degrading intracellular proteins. By mimicking three features of viral infection, we produced ViTPD nanoparticles by biomineralising antibodies enveloped by viral membranes or mixed with IFN-α. The biomineralised shell enhanced the cellular uptake of ViTPD nanoparticles via clathrin-mediated endocytosis. Similar to viral neutralising antibodies entering cells, the Fab region of the antibody released from ViTPD nanoparticles binds the POI, while the Fc region can recruit TRIM21, a key enzyme that continuously consumes during protein degradation. Interestingly, viral membrane components or IFN-α in the ViTPD led to increased TRIM21 expression, which enhanced the efficiency of proteolysis. ViTPD can effectively degrade several POIs, including GFP, FAK, COPZ1 and TREX1. Collectively, our results demonstrate that ViTPD provides a novel design strategy and an efficient nanoplatform for targeting intracellular protein degradation. STATEMENT OF SIGNIFICANCE: Antibody-guided targeted protein degradation (TPD) exhibits superior versatility compared to conventional degradation methods, demonstrating broad compatibility with diverse proteins of interest (POIs) across various cell types. Despite these advantages, significant challenges persist in optimizing cellular antibody internalization efficiency and degradation kinetics. In this study, we developed ViTPD, a biomimetic TPD platform that mimicking three viral infection features: (1) virus-like cellular internalization pathways, (2) virus-neutralizing antibody behavior, and (3) host-mediated protein degradation responses during viral infection. The development of ViTPD provides not only a robust platform for degrading diverse intracellular POIs but also establishes new design principles for next-generation protein degradation systems. This platform establishes new design principles for next-generation TPD systems while expanding therapeutic potential for precision medicine.

A timely inflammatory response is crucial for early viral defense, but uncontrolled inflammation harms the host. Retinoic acid-inducible gene I (RIG-I) has a pivotal role in detecting RNA viruses, yet the regulatory mechanisms governing its sensitivity remain elusive. Here we identify PTEN alpha, an N-terminally extended form of PTEN, as an RNA-binding protein with a preference for the CAUC(G/U)UCAU motif. Using both in vivo and in vitro viral infection assays, we demonstrated that PTEN alpha restricted the host innate immune response, relying on its RNA-binding capacity and phosphatase activity. Mechanistically, PTEN alpha directly bound to viral RNA and enzymatically converted its 5 '-triphosphate to 5 '-monophosphate, thereby reducing RIG-I sensitivity. Physiologically, brain-intrinsic PTEN alpha exerted protective effects against viral inflammation, while peripheral PTEN alpha restricted host antiviral immunity and, to some extent, promoted viral replication. Collectively, our findings underscore the significance of PTEN alpha in modulating viral RNA- and RIG-I-mediated immune recognition, offering potential therapeutic implications for infectious diseases. Yin et al. discover that the phosphatase PTEN alpha acts as an RNA-binding protein, mitigating viral-induced inflammation in the brain by constraining RIG-I activation, suggesting PTEN alpha as a potential therapeutic target for viral infection.

Local recurrence and distal metastasis negatively impact the survival and quality of life in patients with papillary thyroid cancer (PTC). Therefore, identifying potential biomarkers and therapeutic targets for PTC is clinically crucial. In this study, we performed a multiomics analysis that identified a subset of CD36+ proinflammatory macrophages within the tumor microenvironment of PTC. The recruitment of CD36+ macrophages to premalignant regions strongly correlated with unfavorable outcomes in PTC, and the presence of tumor-infiltrating CD36+ macrophages was determined to be a risk factor for recurrence. The CD36+ macrophages exhibited interactions with metabolically active ZCCHC12+ tumor cells. By secreting SPP1, the CD36+ macrophages activated the PI3K-AKT signaling pathway, thereby promoting proliferation of the cancer cells. Dysregulation of iodine metabolism was closely related to the acquisition of the pro-inflammatory phenotype in macrophages. Iodine supplementation inhibited the activation of proinflammatory signaling and impeded the development of CD36+ macrophages by enhancing DUSP2 expression. Overall, our findings shed light on the intricate cross-talk between CD36+ macrophages and ZCCHC12+ tumor cells, providing valuable insights for the treatment and prognosis of PTC.

Supplementary Table S2 - PDF - file 136K, Supplementary Table S2. Relationship of UNC5D methylation, LOH and clinicopathologic characteristics in patients with RCC

T Cell homeostasis The article number 2206344 by Yuxin Yin, Xuehui Zhang, Xuliang Deng, Dan Lu, and co-workers uncovers that peripheral T cells can undergo necroptosis instead of apoptosis when endogenous RPA1 is deleted, which leads to severe lymphopenia and increases the susceptibility of autoinflammatory diseases. Accordingly, chemical or genetic inhibition of necroptosis signaling can ameliorate the inflammatory damage by Rpa1 deficiency and restore host immune homeostasis.

Nephrolithiasis is highly prevalent and associated with the increased risk of kidney cancer. The tumor suppressor von Hippel-Lindau (VHL) is critical for renal cancer development, however, its role in kidney stone disease has not been fully elucidated until now. Here we reported VHL expression was upregulated in renal epithelial cells upon exposure to crystal. Utilizing Vhl+/mu mouse model, depletion of VHL exacerbated kidney inflammatory injury during nephrolithiasis. Conversely, overexpression of VHL limited crystal-induced lipid peroxidation and ferroptosis in a BICD2-depdendent manner. Mechanistically, VHL interacted with the cargo adaptor BICD2 and promoted itsd K48-linked poly-ubiquitination, consequently resulting in the proteasomal degradation of BICD2. Through promoting STAT1 nuclear translocation, BICD2 facilitated IFNγ signaling transduction and enhanced IFNγ-mediated suppression of cystine/glutamate antiporter system Xc-, eventually increasing cell sensitivity to ferroptosis. Moreover, we found that the BRAF inhibitor impaired the association of VHL with BICD2 through triggering BICD2 phosphorylation, ultimately causing severe ferroptosis and nephrotoxicity. Collectively, our results uncover the important role of VHL/BICD2/STAT1 axis in crystal kidney injury and provide a potential therapeutic target for treatment and prevention of renal inflammation and drug-induced nephrotoxicity.

Cancer evades host immune surveillance by virtue of poor immunogenicity. Here, we report an immune suppressor, designated as PTIR1, that acts as a promotor of tumor immune resistance. PTIR1 is selectively induced in human cancers via alternative splicing of DDX58 (RIG-I), and its induction is closely related to poor outcome in patients with cancer. Through blocking the recruitment of leukocytes, PTIR1 facilitates cancer immune escape and tumor-intrinsic resistance to immunotherapeutic treatments. Unlike RIG-I, PTIR1 is capable of binding to the C terminus of UCHL5 and activates its ubiquitinating function, which in turn inhibits immunoproteasome activity and limits neoantigen processing and presentation, consequently blocking T cell recognition and attack against cancer. Moreover, we find that the adenosine deaminase ADAR1 induces A-to-I RNA editing on DDX58 transcript, thus triggering PTIR1 production. Collectively, our data uncover the immunosuppressive role of PTIR1 in tumorigenesis and propose that ADAR1-PTIR1-UCHL5 signaling is a potential cancer immunotherapeutic target.

Tissue-infiltrating neutrophils (TINs) secrete various signaling molecules to establish paracrine communication within the inflammatory milieu. It is imperative to identify molecular mediators that control this secretory phenotype of TINs. The present study uncovers a secretory neutrophil subset that exhibits increased pro-inflammatory cytokine production and enhanced migratory capacity which is highly related with periodontal pathogenesis. Further analysis identifies the OTU domain-containing protein 1 (OTUD1) plays a regulatory role in this secretory neutrophil polarization. In human and mouse periodontitis, the waning of inflammation is correlated with OTUD1 upregulation, whereas severe periodontitis is induced when neutrophil-intrinsic OTUD1 is depleted. Mechanistically, OTUD1 interacts with SEC23B, a component of the coat protein II complex (COPII). By removing the K63-linked polyubiquitin chains on SEC23B Lysine 81, the deubiquitinase OTUD1 negatively regulates the COPII secretory machinery and limits protein ER-to-Golgi trafficking, thus restricting the surface expression of integrin-regulated proteins, CD9 and CD47. Accordingly, blockade of protein transport by Brefeldin A (BFA) curbs recruitment of Otud1-deficient TINs and attenuates inflammation-induced alveolar bone destruction. The results thus identify OTUD1 signaling as a negative feedback loop that limits the polarization of neutrophils with secretory phenotype and highlight the potential application of BFA in the treatment of periodontal inflammation.